6-substituted 2,3,4,5-tetrahydro-1h-benzo[d]azepines as 5-ht2c receptor agonists

ABSTRACT

The present invention provides 6-substituted 2,3,4,5-tetrahydro-1H-benzoazepines of Formula I as selective 5-HT 2C  receptor agonists for the treatment of 5-HT 2C  associated disorders including obesity, obsessive/compulsive disorder, depression, and anxiety: 
     
       
         
         
             
             
         
       
     
     where:
         R 6  is -C≡C-R 10 , -O-R 12 , -S-R 14 , or -NR 24 R 25 ;   and other substituents are as defined in the specification.

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has a richpharmacology arising from a heterogeneous population of at least sevenreceptor classes. The serotonin 5-HT₂ class is further subdivided intoat least three subtypes, designated 5-HT_(2A), 5-HT_(2B), and 5-HT_(2C).The 5-HT_(2C) receptor has been isolated and characterized (Julius, etal., U.S. Pat. No. 4,985,352), and transgenic mice lacking the 5-HT_(2C)receptor have been reported to exhibit seizures and an eating disorderresulting in increased consumption of food (Julius et al., U.S. Pat. No.5,698,766). The 5-HT_(2C) receptor has also been linked to various otherneurological disorders including obesity (Vickers et al.,Psychopharmacology, 167: 274-280 (2003)), hyperphagia (Tecott et al.,Nature, 374: 542-546 (1995)), obsessive compulsive disorder (Martin etal., Pharmacol. Biochem. Behav., 71: 615 (2002); Chou-Green et al.,Physiology & Behavior, 78: 641-649 (2003)), depression (Leysen, Kelder,Trends in Drug Research II, 29: 49-61 (1998)), anxiety (Curr. Opin.Invest. Drugs 2(4), p. 317 (1993)), substance abuse, sleep disorder(Frank et al., Neuropsychopharmacology 27: 869-873 (2002)), hot flashes(EP 1213017 A2), epilepsy (Upton et al., Eur. J. Pharmacol., 359: 33(1998); Fitzgerald, Ennis, Annual Reports in Medicinal Chemistry, 37:21-30 (2002)), and hypogonadism (Curr. Opin. Invest. Drugs 2(4), p. 317(1993)).

Certain substituted 2,3,4,5-tetrahydro-1H-benzo[d]azepine compounds havebeen disclosed as useful therapeutics as for example:

U.S. Pat. No. 4,265,890 describes certain substituted2,3,4,5-tetrahydro-1H-benzo[d]azepine compounds as dopaminergic receptorantagonists for use as antipsychotics and antiemetics, inter alia.

EP 0 285 287 describes certain substituted2,3,4,5-tetrahydro-1H-benzo[d]azepine compounds for use as agents totreat gastrointestinal motility disorders, inter alia.

WO 93/03015 and WO 93/04686 describe certain substituted2,3,4,5-tetrahydro-1H-benzo[d]azepine compounds as alpha-adrenergicreceptor antagonists for use as agents to treat hypertension andcardiovascular diseases in which changes in vascular resistance aredesirable, inter alia.

WO 02/074746 A1 describes certain substituted2,3,4,5-tetrahydro-1H-benzo[d]azepine compounds as 5-HT_(2C) agonistsfor the treatment of hypogonadism, obesity, hyperphagia, anxiety,depression, sleep disorder, inter alia.

WO 03/006466 A1 describes certain substituted tricyclichexahydroazepinoindole and indoline compounds as 5-HT ligands andconsequently their usefulness for treating diseases wherein modulationof 5-HT activity is desired.

High affinity 5-HT_(2C) receptor agonists would provide usefultherapeutics for the treatment of the above mentioned 5-HT_(2C)receptor-associated disorders including obesity, hyperphagia,obsessive/compulsive disorder, depression, anxiety, substance abuse,sleep disorder, hot flashes, and hypogonadism. High affinity 5-HT_(2C)receptor agonists that are also selective for the 5-HT_(2C) receptor,would provide such therapeutic benefit without the undesirable adverseevents associated with current therapies. Achieving selectivity for the5-HT_(2C) receptor, particularly as against the 5-HT_(2A) and 5-HT_(2B)receptors, has proven difficult in designing 5-HT_(2C) agonists.5-HT_(2A) receptor agonists have been associated with problematichallucinogenic adverse events. (Nelson et al., Naunyn-Schmiedeberg'sArch. Pharm., 359: 1-6 (1999)). 5-HT_(2B) receptor agonists have beenassociated with cardiovascular related adverse events, such asvalvulopathy. (V. Setola et al., Mol. Pharmacology, 63: 1223-1229(2003), and ref. cited therein).

Previous references to substituted 2,3,4,5-tetrahydro-1H-benzo[d]azepinecompounds as potential therapeutics have predominately recited theiruses as alpha adrenergic and/or dopaminergic modulators. Adrenergicmodulators are often associated with the treatment of cardiovasculardiseases (Frishman, Kotob, Journal of Clinical Pharmacology, 39: 7-16(1999)). Dopaminergic receptors are primary targets in the treatment ofschizophrenia and Parkinson's disease (Seeman, Van Tol, Trends inPharmacological Sciences, 15: 264-270 (1994)). It will be appreciated bythose skilled in the art that selectivity as against these and otherphysiologically important receptors will generally also be preferredcharacteristics for therapeutics for the specific treatment of 5-HT_(2C)associated disorders as described above.

The present invention provides selective 5-HT_(2C) agonist compounds ofFormula I:

where:

-   R¹ is hydrogen, fluoro, or (C₁-C₃)alkyl;-   R², R³, and R⁴ are each independently hydrogen, methyl, or ethyl;-   R⁵ is hydrogen, fluoro, methyl, or ethyl;-   R⁶ is —C≡C—R¹⁰, —O—R¹²; —S—R¹⁴, or —NR²⁴R²⁵;-   R⁷ is hydrogen, halo, cyano, (C₁-C₆)alkyl optionally substituted    with 1 to 6 fluoro substituents, (C₂-C₆)alkenyl optionally    substituted with 1 to 6 fluoro substituents, (C₃-C₇)cycloalkyl,    (C₁-C₆)alkoxy optionally substituted with 1 to 6 fluoro    substituents, (C₁-C₆)alkylthio optionally substituted with 1 to 6    fluoro substituents, Ph¹-(C₀-C₃)alkyl, Ph¹-(C₀-C₃)alkyl-O—, or    Ph¹-(C₀-C₃)alkyl-S—;-   R⁸ is hydrogen, halo, cyano, or —SCF₃;-   R⁹ is hydrogen, halo, cyano, —CF₃, —SCF₃, or (C₁-C₃)alkoxy    optionally substituted with 1 to 6 fluoro substituents;-   R¹⁰ is —CF₃, ethyl substituted with 1 to 5 fluoro substituents,    (C₃-C₆) alkyl optionally substituted with 1 to 6 fluoro    substituents, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl, Ar¹—(C₀-C₃)alkyl,    Ph¹-(C₀-C₃)alkyl, or    3-(C₁-C₄)alkyl-2-oxo-imidazolidin-1-yl-(C₁-C₃)alkyl;-   R¹² is Ph²-(C₁-C₃)alkyl, Ar²—(C₁-C₃)alkyl,    (C₁-C₆)alkyl-S—(C₂-C₆)alkyl, (C₃-C₇)cycloalkyl-S—(C₂-C₆)alkyl,    phenyl-S—(C₂-C₆)alkyl, Ph²-S—(C₂-C₆)alkyl,    phenylcarbonyl-(C₁-C₃)alkyl, Ph²-C(O)—(C₁-C₃)alkyl,    (C₁-C₆)alkoxycarbonyl(C₃-C₆)alkyl,    (C₃-C₇)cycloalkyl-OC(O)—(C₃-C₆)alkyl,    phenyloxycarbonyl-(C₃-C₆)alkyl, Ph²-OC(O)—(C₃-C₆)alkyl,    Ar²—OC(O)—(C₃-C₆)alkyl, (C₃-C₇)cycloalkyl-NH—C(O)—(C₂-C₄)alkyl-,    Ph¹-NH—C(O)—(C₂-C₄)alkyl-, Ar²—NH—C(O)—(C₂-C₄)alkyl-, or    R¹³—C(O)NH—(C₂-C₄)alkyl;-   R¹³ is (C₃-C₇)cycloalkyl(C₀-C₃)alkyl, Ph², Ar², or (C₁-C₃)alkoxy    optionally substituted with 1 to 6 fluoro substituents, Ph¹-NH— or    N-linked Het¹;-   R¹⁴ is Ar² which is not N-linked to the sulfur atom, Ph², R¹⁵-L-,    tetrahydrofuranyl, tetrahydropyranyl, or phenyl-methyl substituted    on the methyl moiety with a substituent selected from the group    consisting of (C₁-C₃)-n-alkyl substituted with hydroxy,    (C₁-C₃)alkyl-O—(C₁-C₂)-n-alkyl, (C₁-C₃)alkyl-C(O)—(C₀-C₂)-n-alkyl,    and (C₁-C₃)alkyl-O—C(O)—(C₀-C₂)-n-alkyl,    -   wherein when R¹⁴ is Ph² or Ar², wherein Ar² is pyridyl, then R¹⁴        may also, optionally be substituted with phenyl-CH═CH— or        phenyl-C≡C—,        -   said phenyl-CH═CH— or phenyl-C≡C— being optionally further            substituted with 1 to 3 substituents independently selected            from the group consisting of halo, cyano, —SCF₃,            (C₁-C₆)alkyl optionally further substituted with 1 to 6            fluoro substituents, and (C₁-C₆)alkoxy optionally further            substituted with 1 to 6 fluoro substituents, and    -   wherein when Ar² is pyridyl, the pyridyl may alternatively,        optionally be substituted with R²⁸R²⁹N—C(O)—, and optionally        further substituted with one methyl, —CF₃, cyano, or —SCF₃        substituent, or with 1 to 2 halo substituents, and    -   wherein the tetrahydrofuranyl and tetrahydropyranyl may        optionally be substituted with an oxo substituent, or with one        or two groups independently selected from methyl and —CF₃;-   R⁵ is —OR¹⁶, cyano, —SCF₃, Ph², A, quinolinyl, isoquinolinyl,    cinnolinyl, quinazolinyl, phthalimido, benzothiophenyl optionally    substituted at the 2-position with phenyl or benzyl, benzothiazolyl    optionally substituted at the 2-position with phenyl or benzyl,    benzothiadiazolyl optionally substituted with phenyl or benzyl,    2-oxo-dihydroindol-1-yl optionally substituted at the 3 position    with gem dimethyl or (C₁-C₆)alkyl optionally further substituted    with 1 to 6 fluoro substituents, 2-oxo-dihydroindol-5-yl optionally    substituted at the 3 position with gem dimethyl or (C₁-C₆)alkyl    optionally further substituted with 1 to 6 fluoro substituents,    2-oxo-imidazolidin-1-yl optionally substituted at the 3 position    with gem dimethyl or (C₁-C₆)alkyl optionally further substituted    with 1 to 6 fluoro substituents, 2-oxo-tetrahydropyridinyl    optionally substituted at the 3 or 4 position with gem dimethyl or    (C₁-C₆)alkyl optionally further substituted with 1 to 6 fluoro    substituents, 2-oxo-tetrahydroquinolin-1-yl optionally substituted    at the 3 position with gem dimethyl or (C₁-C₆)alkyl optionally    further substituted with 1 to 6 fluoro substituents,    2-oxo-dihydrobenzimidazol-1-yl optionally substituted at the 3    position with gem dimethyl or (C₁-C₆)alkyl optionally further    substituted with 1 to 6 fluoro substituents, —NR¹⁷R¹⁸, —C(O)R²², or    a saturated heterocycle selected from the group consisting of    pyrrolidinyl, piperidinyl, morpholinyl, and thiomorpholinyl,    tetrahydrofuranyl, and tetrahydropyranyl,    -   wherein Ph² and Ar² when Ar² is pyridyl, may also optionally be        substituted with phenyl-CH═CH— or phenyl-C≡C—,        -   said phenyl-CH═CH— and phenyl-C≡C— being optionally further            substituted on the phenyl moiety with 1 to 3 substituents            independently selected from the group consisting of halo,            cyano, —SCF₃, (C₁-C₆)alkyl optionally further substituted            with 1 to 6 fluoro substituents, and (C₁-C₆)alkoxy            optionally further substituted with 1 to 6 fluoro            substituents, and    -   wherein Ar² may alternatively, optionally be substituted with a        substituent selected from the group consisting of        (C₃-C₇)cycloalkyl-(C₀-C₃)alkyl, Het¹-(C₀-C₃)alkyl,        pyridyl-(C₀-C₃)alkyl, and phenyl-(C₀-C₃)alkyl, and optionally        further substituted with one methyl, —CF₃, cyano, or —SCF₃        substituent, or with 1 to 2 halo substituents,        -   said pyridyl-(C₀-C₃)alkyl and phenyl-(C₀-C₃)alkyl optionally            being further substituted with 1-3 substituents            independently selected from halo, —CH₃, —OCH₃, —CF₃, —OCF₃,            —CN, and —SCF₃, and    -   wherein when Ar² is pyridyl, the pyridyl may alternatively,        optionally be substituted with R²⁸R²⁹N—C(O)—, or        (C₁-C₆)alkyl-C(O)— optionally substituted with 1 to 6 fluoro        substituents, and may be optionally further substituted with one        methyl, —CF₃, cyano, or —SCF₃ substituent, or with 1 to 2 halo        substituents, and    -   wherein when Ar² is thiazolyl, the thiazolyl may alternatively,        optionally be substituted with        (C₃-C₇)cycloalkyl-(C₀-C₃)alkyl-NH—, and    -   wherein the pyrrolidinyl, piperidinyl, morpholinyl, and        thiomorpholinyl is substituted with oxo- on a carbon atom        adjacent to the ring nitrogen atom, or is N-substituted with a        substituent selected from the group consisting of        -   (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl,        -   (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-C(O)—,        -   (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-S(O)₂—,            Ph¹-(C₀-C₃)alkyl-C(O)—, and Ph¹-(C₀-C₃)alkyl-S(O)₂—, and    -   may optionally be further substituted with 1 or 2 methyl or —CF₃        substituents, and when oxo-substituted, may optionally be        further N-substituted with a substituent selected from the group        consisting of        -   (C₁-C₆)alkyl optionally further substituted with 1 to 6            fluoro substituents, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl, and            Ph¹-(C₀-C₃)alkyl, and    -   wherein tetrahydrofuranyl and tetrahydropyranyl may optionally        be substituted with an oxo substituent, and/or with one or two        groups independently selected from methyl and CF₃;-   L is branched or unbranched (C₁-C₆)alkylene, except when R¹⁵ is    —NR¹⁷R¹⁸ or Ar²-N-linked to L, in which case L is branched or    unbranched (C₂-C₆)alkylene, and when L is methylene or ethylene, L    may optionally be substituted with gem-ethano or with 1 to 2 fluoro    substituents, and when R¹⁵ is Ph², Ar², or a saturated heterocycle,    L may alternatively, optionally be substituted with a substituent    selected from the group consisting of hydroxy, cyano, —SCF₃,    (C₁-C₆)alkoxy optionally further substituted with 1 to 6 fluoro    substituents, (C₁-C₆)alkoxycarbonyl optionally further substituted    with 1 to 6 fluoro substituents, (C₁-C₆)alkylcarbonyloxy optionally    further substituted with 1 to 6 fluoro substituents,    (C₃-C₇)cycloalkyl-(C₀-C₃)alkyl-O—,    -   (C₃-C₇)cycloalkyl-(C₀-C₃)alkyl-O—C(O)—, and        (C₃-C₇)cycloalkyl-(C₀-C₃)alkyl-C(O)—O—;-   R¹⁶ is hydrogen, (C₁-C₆)alkyl optionally substituted with 1 to 6    fluoro substituents, (C₁-C₆)alkylcarbonyl,    (C₃-C₇)cycloalkyl(C₀-C₃)alkyl, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-C(O)—,    Ph¹-(C₀-C₃)alkyl, Ph¹-(C₀-C₃)alkyl-C(O)—, Ar²—(C₀-C₃)alkyl, or    Ar²—(C₀-C₃)alkyl-C(O)—,-   R¹⁷ is (C₁-C₄)alkyl optionally substituted with 1 to 6 fluoro    substituents, t-butylsulfonyl, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-C(O)—,    (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-sulfonyl, Ph¹-(C₀-C₃)alkyl,    Ph¹-(C₀-C₃)alkyl-C(O)—, Ph¹-(C₀-C₃)alkylsulfonyl, Ar²—(C₀-C₃)alkyl,    Ar²—(C₀-C₃)alkyl-C(O)—, Ar²—(C₀-C₃)alkylsulfonyl, R¹⁹OC(O)—, or    R²⁰R²¹NC(O)—;-   R¹⁸ is hydrogen or (C₁-C₄)alkyl optionally substituted with 1 to 6    fluoro substituents, or R¹⁷ and R¹⁸, taken together with the    nitrogen atom to which they are attached form Het¹ where Het¹ is    substituted with oxo- on a carbon atom adjacent to the ring nitrogen    atom, or    -   R¹⁷ and R¹⁸, taken together with the nitrogen atom to which they        are attached, form an aromatic heterocycle selected from the        group consisting of pyrolyl, pyrazolyl, imidazolyl,        1,2,3-triazolyl, and 1,2,4-triazolyl,        -   said aromatic heterocycle optionally being substituted with            1 to 2 halo substituents, or substituted with 1, to 2            (C₁-C₄)alkyl substituents optionally further substituted            with 1 to 3 fluoro substituents, or mono-substituted with            fluoro, nitro, cyano, —SCF₃, or (C₁-C₄)alkoxy optionally            further substituted with 1 to 3 fluoro substituents, and            optionally further substituted with a (C₁-C₄)alkyl            substituent optionally further substituted with 1 to 3            fluoro substituents;-   R¹⁹ is (C₁-C₆)alkyl optionally substituted with 1 to 6 fluoro    substituents, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl, Ar²—(C₀-C₃)alkyl, or    Ph¹-(C₀-C₃)alkyl,-   R²⁰ is (C₁-C₆)alkyl optionally substituted with 1 to 6 fluoro    substituents, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl, Ar²—(C₀-C₃)alkyl, or    Ph¹-(C₀-C₃)alkyl,-   R²¹ is hydrogen or (C₁-C₄)alkyl optionally substituted with 1 to 6    fluoro substituents, or R²⁰ and R²¹, taken together with the    nitrogen atom to which they are attached, form Het¹;-   R²² is (C₁-C₆)alkyl optionally substituted with 1 to 6 fluoro    substituents, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl, R²³—O—,    Ph¹-(C₀-C₃)alkyl, Ar²—(C₀-C₃)alkyl, or R³²R³³N—,-   R²³ is (C₁-C₆)alkyl optionally substituted with 1 to 6 fluoro    substituents, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl, Ph¹-(C₀-C₃)alkyl, or    Ar²—(C₀-C₃)alkyl;-   R²⁴ is (C₁-C₆)alkoxy(C₂-C₅)alkyl optionally substituted with 1 to 6    fluoro substituents, (C₁-C₆)alkylthio(C₂-C₅)alkyl optionally    substituted with 1 to 6 fluoro substituents,    (C₃-C₇)cycloalkyl(C₀-C₁)alkyl-O—(C₁-C₅)alkyl,    (C₃-C₇)cycloalkyl(C₀-C₁)alkyl-S—(C₁-C₅)alkyl, phenyl(C₁-C₃) n-alkyl,    Ph²-(C₁-C₃)-n-alkyl, Ar²(C₀-C₃) n-alkyl,    phenyl(C₀-C₁)alkyl-O—(C₁-C₅)alkyl, phenyl(C₀-C₁)alkyl-S—(C₁-C₅)alkyl    Ph¹-(C₀-C₁)alkyl-C(O)NH—(C₂-C₄)alkyl,    Ph¹-(C₀-C₁)alkyl-NH—C(O)NH—(C₂-C₄)alkyl,    pyridyl-(C₀-C₁)alkyl-C(O)NH—(C₂-C₄)alkyl,    pyridyl-(C₀-C₁)alkyl-NH—C(O)NH—(C₂-C₄)alkyl, or Ar³(C₁-C₂)alkyl,    -   where Ar³ is a bi-cyclic moiety selected from a group consisting        of indanyl, indolyl, dihydrobenzofuranyl, benzofuranyl,        benzothiophenyl, benzoxazolyl, benzothiazolyl,        benzo[1,3]dioxolyl, naphthyl, dihydrobenzopyranyl, quinolinyl,        isoquinolinyl, and benzo[1,2,3]thiadiazolyl,        -   said Ar³ optionally being substituted with (C₁-C₆)alkyl            optionally further substituted with 1 to 6 fluoro            substituents, phenyl(C₀-C₁)alkyl optionally further            substituted with 1 to 6 fluoro substituents, or substituted            with (C₃-C₇)cycloalkyl(C₀-C₃)alkyl, or substituted with 1-3            substituents independently selected from the group            consisting of halo, oxo, methyl, and —CF₃,        -   said phenyl(C₁-C₃) n-alkyl, Ph²-(C₁-C₃) n-alkyl, or            Ar²(C₀-C₃) n-alkyl optionally being substituted on the            n-alkyl moiety when present with (C₁-C₃)alkyl, dimethyl,            gem-ethano, 1 to 2 fluoro substituents, or            (C₁-C₆)alkyl-C(O)—,        -   said Ar²(C₀-C₃) n-alkyl being alternatively optionally            substituted with a substituent selected from the group            consisting of (C₃-C₇)cycloalkyl-(C₀-C₃)alkyl,            Het¹-(C₀-C₃)alkyl, pyridyl-(C₀-C₃)alkyl,            phenyl-(C₀-C₃)alkyl, pyridyl-(C₀-C₃)alkyl-NH—,            phenyl-(C₀-C₃)alkyl-NH—, (C₁-C₆)alkyl-S—, and            (C₃-C₇)cycloalkyl-(C₀-C₃)alkyl-S—, and optionally further            substituted with one methyl, —CF₃, cyano, or —SCF₃            substituent, or with 1 to 2 halo substituents,            -   said pyridyl-(C₀-C₃)alkyl and phenyl-(C₀-C₃)alkyl                optionally being further substituted with 1-3                substituents independently selected from halo, —CH₃,                —OCH₃, —CF₃, —OCF₃, —CN, and —SCF₃, and        -   said Ph²-(C₁-C₃) n-alkyl and Ar²(C₀-C₃) n-alkyl where Ar² is            pyridyl, also optionally being substituted on the phenyl or            Ar² moiety, respectively, with phenyl-CH═CH— or phenyl-C≡C—,            -   said phenyl-CH═CH— or phenyl-C≡C— being optionally                further substituted with 1 to 3 substituents                independently selected from the group consisting of                halo, cyano, —SCF₃, (C₁-C₆)alkyl optionally further                substituted with 1 to 6 fluoro substituents, and                (C₁-C₆)alkoxy optionally further substituted with 1 to 6                fluoro substituents, and        -   said Ar²(C₀-C₃) n-alkyl where Ar² is pyridyl, alternatively,            optionally being substituted with (C₁-C₆)alkyl-C(O)— or            R²⁸R²⁹N—C(O)—, and optionally further substituted with one            methyl, —CF₃, cyano, or —SCF₃ substituent, or with 1 to 2            halo substituents,        -   said phenyl(C₀-C₁)alkyl-O—(C₁-C₅)alkyl, or            phenyl(C₀-C₁)alkyl-S—(C₁-C₅)alkyl optionally being            substituted on the phenyl moiety with (C₁-C₂)—S(O)₂—, or            with 1 to 5 independently selected halo substituents, or            with 1 to 3 substituents independently selected from the            group consisting of halo, cyano, —SCF₃, (C₁-C₆)alkyl            optionally further substituted with 1 to 6 fluoro            substituents, and (C₁-C₆)alkoxy optionally further            substituted with 1 to 6 fluoro substituents, and        -   said pyridyl-(C₀-C₁)alkyl-C(O)NH—C₂-C₄)alkyl and            pyridyl-(C₀-C₁)alkyl-NH—C(O)NH—(C₂-C₄)alkyl optionally being            substituted on the pyridyl moiety with methyl, —CF₃, or 1 to            3 halo substituents;-   R²⁵ is hydrogen, (C₁-C₃)alkyl optionally substituted with 1 to 6    fluoro substituents, or alkyl;-   R⁶ is hydrogen, (C₁-C₆)alkyl optionally substituted with 1 to 6    fluoro substituents, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl;-   R²⁷ is hydrogen or (C₁-C₄)alkyl optionally substituted with 1 to 6    fluoro substituents, or-   R²⁶ and R²⁷, taken together with the nitrogen atom to which they are    attached, form Het¹;-   R²⁸ is (C₁-C₈)alkyl optionally substituted with 1 to 6 fluoro    substituents, (C₃-C₈)cycloalkyl(C₀-C₃)alkyl,    tetrahydropyran-3-yl(C₀-C₃)alkyl, tetrahydropyran-4-yl(C₀-C₃)alkyl,    tetrahydrofuranyl(C₀-C₃)alkyl, Ph¹-(C₀-C₂) n-alkyl, or Ar²—(C₀-C₂)    n-alkyl,    -   said Ph¹-(C₀-C₂) n-alkyl and Ar²—(C₀-C₂) n-alkyl optionally        being substituted on the alkyl moiety when present with        (C₁-C₃)alkyl, dimethyl, or gem-ethano;-   R²⁹ is hydrogen or (C₁-C₃)alkyl;-   R³⁰ is hydrogen, (C₁-C₆)alkyl optionally substituted with 1 to 6    fluoro substituents, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl,    Ph¹-(C₀-C₃)alkyl, or Ar²(C₀-C₃)alkyl,-   R³¹ is hydrogen or (C₁-C₆)alkyl optionally substituted with 1 to 6    fluoro substituents, or R³⁰ and R³¹, taken together with the    nitrogen atom to which they are attached, form Het¹,    -   said Het¹ also optionally being substituted with phenyl        optionally further substituted with 1 to 3 halo substituents;-   R³² and R³³ are each independently hydrogen or (C₁-C₆)alkyl    optionally substituted with 1 to 6 fluoro substituents, or R³² and    R³³, taken together with the nitrogen atom to which they are    attached, form Het¹, or R³² is Ph¹(C₀-C₁)alkyl provided that R³³ is    hydrogen;-   Ar¹ is an aromatic heterocycle substituent selected from the group    consisting of furanyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl,    pyridyl, and pyridazinyl, any of which may optionally be substituted    with 1 to 3 substituents independently selected from the group    consisting of halo, (C₁-C₃)alkyl, (C₁-C₃)alkoxy, —CF₃, —O—CF₃,    nitro, cyano, and trifluoromethylthio;-   Ar² is an aromatic heterocycle substituent selected from the group    consisting of pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,    1,2,4-triazolyl, furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl,    1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl,    isothiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl,    pyridazinyl, and benzimidazolyl, any of which may optionally be    substituted with 1 to 3 substituents independently selected from the    group consisting of halo, cyano, —SCF₃, (C₁-C₆)alkyl optionally    further substituted with 1 to 6 fluoro substituents, and    (C₁-C₆)alkoxy optionally further substituted with 1 to 6 fluoro    substituents, and wherein pyridyl and pyridazinyl may also    optionally be substituted with (C₁-C₆)alkylamino optionally further    substituted with 1 to 6 fluoro substituents,    (C₃-C₇)cycloalkyl(C₀-C₃)alkyl, or    (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-amino;-   Het¹ is a saturated, nitrogen-containing heterocycle substituent    selected from the group consisting of azetidinyl, pyrrolidinyl,    piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl,    homomorpholinyl, and homothiomorpholinyl, any of which may    optionally be substituted with (C₁-C₆)alkyl or with 2 methyl    substituents;-   Het² is a saturated, oxygen-containing heterocycle substituent    selected from the group consisting of tetrahydrofuranyl and    tetrahydropyranyl, any of which may optionally be substituted with    (C₁-C₆)alkyl or with 2 methyl substituents;-   Ph¹ is phenyl optionally substituted with 1 to 5 independently    selected halo substituents, or with 1 to 3 substituents    independently selected from the group consisting of halo, cyano,    —SCF₃, (C₁-C₆)alkyl optionally further substituted with 1 to 6    fluoro substituents, and (C₁-C₆)alkoxy optionally further    substituted with 1 to 6 fluoro substituents;-   Ph² is phenyl substituted with:    -   a) 1 to 5 independently selected halo substituents; or    -   b) 1 to 3 substituents independently selected from the group        consisting of halo, cyano, —SCF₃, nitro, hydroxy, (C₁-C₆)alkyl        optionally further substituted with 1 to 6 fluoro substituents,        and (C₁-C₆)alkoxy optionally further substituted with 1 to 6        fluoro substituents; or    -   c) 0, 1, or 2 substituents independently selected from the group        consisting of halo, cyano, —SCF₃, methyl, —CF₃, methoxy, —OCF₃,        nitro, and hydroxy, together with one substituent selected from        the group consisting of        -   i) (C₁-C₁₀)alkyl optionally further substituted with 1 to 6            fluoro substituents or mono-substituted with hydroxy,            (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl(C₀-C₃)alkyloxy,            Het²-(C₀-C₃)alkyloxy, Ph¹-(C₀-C₃)alkyloxy,        -   ii) (C₁-C₁₀)alkoxy-(C₀-C₃)alkyl optionally further            substituted with 1 to 6 fluoro substituents, and optionally            further substituted with hydroxy,        -   iii) (C₁-C₆)alkyl-C(O)—(C₀-C₅)alkyl optionally further            substituted with 1 to 6 fluoro substituents,        -   iv) carboxy,        -   v) (C₁-C₆)alkoxycarbonyl optionally further substituted with            1 to 6 fluoro substituents,        -   vi) (C₁-C₆)alkyl-C(O)—(C₀-C₃)—O— optionally further            substituted with 1 to 6 fluoro substituents,        -   vii) (C₁-C₆)alkylthio-(C₀-C₅)alkyl optionally further            substituted with 1 to 6 fluoro substituents,        -   viii) (C₁-C₆)alkylsulfinyl-(C₀-C₅)alkyl optionally further            substituted with 1 to 6 fluoro substituents,        -   ix) (C₁-C₆)alkylsulfonyl-(C₀-C₅)alkyl optionally further            substituted with 1 to 6 fluoro substituents,        -   x) (C₁-C₆)alkylsulfonyl-(C₀-C₃)alkyl-O— optionally further            substituted with 1 to 6 fluoro substituents,        -   xi) (C₃-C₇)cycloalkyl(C₀-C₃)alkyl, optionally further            substituted on the cycloalkyl with 1 to 4 substituents            selected from methyl and fluoro,        -   xii) (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-O—, optionally further            substituted on the cycloalkyl with 1 to 4 substituents            selected from methyl and fluoro,        -   xiii) (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-C(O)—,        -   xiv) (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-O—C(O)—,        -   xv) (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-S—,        -   xvi) (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-S(O)—,        -   xvii) (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-S(O)₂—,        -   xviii) Ph¹-(C₀-C₃)alkyl, optionally substituted on the alkyl            moiety with 1 to 2 fluoro substituents,        -   xix) Ph¹-(C₀-C₃)alkyl-O—, optionally substituted on the            alkyl moiety with 1 to 2 fluoro substituents        -   xx) Ph¹-(C₀-C₃)alkyl-C(O)—,        -   xxi) Ph¹-(C₀-C₃)alkyl-O—C(O)—,        -   xxii) Ph¹-(C₀-C₃)alkyl-C(O)—(C₀-C₃)alkyl-O—,        -   xxiii) Ph¹-(C₀-C₃)alkylthio,        -   xxiv) Ph¹-(C₀-C₃)alkylsulfinyl,        -   xxv) Ph¹-(C₀-C₃)alkylsulfonyl,        -   xxvi) Ar²(C₀-C₃)alkyl,        -   xxvii) Ar²(C₀-C₃)alkyl-O—        -   xxviii) Ar²—(C₀-C₃)alkyl-S—,        -   xxix) Ar²(C₀-C₃)alkyl-C(O)—,        -   xxx) Ar²(C₀-C₃)alkyl-C(S)—,        -   xxxi) Ar²—(C₀-C₃)alkylsulfinyl,        -   xxxii) Ar²—(C₀-C₃)alkylsulfonyl,        -   xxxiii) Het¹(C₀-C₃)alkyl-C(O) optionally substituted on the            Het¹ moiety with Ph¹,        -   xxxiv) Het¹(C₀-C₃)alkyl-C(S)— optionally substituted on the            Het¹ moiety with Ph²,        -   xxxv) N-linked Het¹-C(O)—(C₀-C₃)alkyl-O—,        -   xxxvi) Het²-(C₀-C₃)alkyloxy,        -   xxxvii) R²⁶R²⁷N—,        -   xxxviii) R²⁸R²⁹N—(C₁-C₃)alkoxy,        -   xxxix) R²⁸R²⁹N—C(O)—,        -   xl) R²⁸R²⁹N—C(O)—(C₁-C₃)alkyl-O—,        -   xli) R²⁸R²⁹N—C(S)—,        -   xlii) R³⁰R³¹N—S(O)₂—,        -   xliii) HON═C(CH₃)—, and        -   xliv) HON═C(Ph¹)-,            or a pharmaceutically acceptable salt thereof, subject to            the following provisos:    -   a) no more than two of R¹, R², R³, R⁴, and R⁵ may be other than        hydrogen;    -   b) when R² is methyl, then R¹, R³, R⁴, and R⁵ are each hydrogen;    -   c) when R³ is methyl, then R² and R⁴ are each hydrogen;    -   d) when R³ is methyl, R⁷ and R⁸ are each —H, and R¹, R², R⁴, R⁵,        and R⁹ are each hydrogen, then R⁶ is other than cyclohexylthio,        furanylthio, or phenylthio; and    -   e) When R¹² is Ar²—(C₁-C₃)alkyl, then R⁷ is other than hydrogen        or R⁹ is other than chloro.

This invention also provides pharmaceutical compositions which comprisea compound of Formula I, or a pharmaceutically acceptable salt thereof,in association with a pharmaceutically acceptable carrier, diluent, orexcipient.

In another aspect of the present invention, there is provided a methodfor increasing activation of the 5-HT_(2C) receptor in mammalscomprising administering to a mammal in need of such activation aneffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.

The present invention also provides a method for treating obesity inmammals comprising administering to a mammal in need of such treatmentan effective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.

The present invention also provides a method for treatingobsessive/compulsive disorder in mammals comprising administering to amammal in need of such treatment an effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention provides a method for treatingdepression in mammals comprising administering to a mammal in need ofsuch treatment an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

Furthermore, the present invention provides a method for treatinganxiety in mammals comprising administering to a mammal in need of suchtreatment an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

In preferred embodiments of the above methods of treatment utilizing acompound of Formula I, or a pharmaceutically acceptable salt thereof,the mammal is a human.

In another aspect of the present invention, there is provided a compoundof Formula I for use in selectively increasing activation of the5-HT_(2C) receptor and/or for use in treating a variety of disordersassociated with decreased activation of 5-HT_(2C) receptors. Preferredembodiments of this aspect of the invention include a compound ofFormula I for use in the treatment of obesity, hyperphagia,obsessive/compulsive disorder, depression, anxiety, substance abuse,sleep disorder, hot flashes, and/or hypogonadism. Particularly preferredembodiments of this aspect of the invention include the treatment ofobesity, obsessive/compulsive disorder, depression, and/or anxiety.

In another aspect of the present invention, there is provided the use ofone or more compounds of Formula I in the manufacture of a medicamentfor the activation of 5-HT_(2C) receptors in a mammal. In preferredembodiments of this aspect of the invention, there is provided the useof one or more compounds of Formula I in the manufacture of a medicamentfor the treatment of obesity, hyperphagia, obsessive/compulsivedisorder, depression, anxiety, substance abuse, sleep disorder, hotflashes, and/or hypogonadism. Particularly preferred embodiments of thisaspect of the invention include the use of one or more compounds ofFormula I in the manufacture of medicaments for the treatment ofobesity, obsessive/compulsive disorder, depression, and/or anxiety.

Additionally, the present invention provides a pharmaceuticalformulation adapted for the treatment of obesity, or for the treatmentof obsessive/compulsive disorder, or for the treatment of depression, orfor the treatment of anxiety, each of which comprise a compound ofFormula I in association with a pharmaceutically acceptable carrier,diluent or excipient.

In those instances where the disorders which can be treated by 5-HT_(2C)agonists are known by established and accepted classifications, theirclassifications can be found in various sources. For example, atpresent, the fourth edition of the Diagnostic and Statistical Manual ofMental Disorders (DSM-IV™) (1994, American Psychiatric Association,Washington, D.C.), provides a diagnostic tool for identifying many ofthe disorders described herein. Also, the International Classificationof Diseases, Tenth Revision (ICD-10), provides classifications for manyof the disorders described herein. The skilled artisan will recognizethat there are alternative nomenclatures, nosologies, and classificationsystems for disorders described herein, including those as described inthe DSM-IV and ICD-10, and that terminology and classification systemsevolve with medical scientific progress.

The general chemical terms used throughout have their usual meanings.For example, the term “alkyl” refers to a branched or unbranchedsaturated hydrocarbon group. The term “n-alkyl” refers to an unbranchedalkyl group. By way of illustration, but without limitation, the term“(C₁-C₂)alkyl” refers to methyl and ethyl. The term “(C₁-C₃) n-alkyl”refers to methyl, ethyl, and propyl. The term “(C₁-C₃)alkyl” refers tomethyl, ethyl, propyl, and isopropyl. The term “(C₁-C₄) n-alkyl” refersto methyl, ethyl, n-propyl, and n-butyl. The term “(C₁-C₄)alkyl” refersto methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, andtert-butyl. The term “(C₁-C₆)alkyl” refers to all branched andunbranched alkyl groups having from one to six carbon atoms. The term“(C₃-C₆)alkyl” refers to all branched and unbranched alkyl groups havingfrom three to six carbon atoms. The term “(C₂-C₆)alkyl” refers to allbranched and unbranched alkyl groups having from two to six carbonatoms.

(C_(x)-C_(y))alkyl may also be used in conjunction with othersubstituents to indicate a branched or unbranched saturated hydrocarbonlinker for the substituent, where x and y indicate the range of carbonatoms permitted in the linker moiety. By way of illustration, butwithout limitation, —(C₀-C₁)alkyl refers to a single bond or a methylenelinker moiety; —(C₀-C₂)alkyl refers to a single bond, methylene,methyl-methylene, or ethylene linker moiety; —(C₀-C₃)alkyl furtherincludes trimethylene, alpha- or beta-methyl ethylene, or ethylmethylene. —(C₁-C₂)alkyl, —(C₁-C₃)alkyl, —(C₁-C₄)alkyl, and—(C₁-C₆)alkyl refer to branched or unbranched alkylene linkers havingfrom 1 to 2, 3, 4, or 6 carbons, respectively.

The term “alkenyl” refers to a branched or unbranched unsaturatedhydrocarbon group. By way of illustration, but without limitation, theterm “(C₂-C₆)alkenyl” refers to a branched or unbranched hydrocarbongroup having from 2 to 6 carbon atoms and 1 or more carbon-carbon doublebonds. Allyl means a propyl-2-en-1-yl moiety (CH₂═CH—CH₂—).

The term “(C₃-C₇)cycloalkyl” refers to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkylalkyl refers to acycloalkyl moiety linked through a branched or unbranched alkylenelinker, as for example, but without limitation, —CH₂—, —CH₂CH₂—,—CH(CH₃)—, —CH₂CH₂CH₂—, —CH₂CH(CH₃)—, —CH(CH₃)CH₂—, —CH(CH₂CH₃)—, andthe like. (C₃-C₇)cycloalkyl(C₀-C_(1, 2 or 3))alkyl, refers tocycloalkyls linked through a single bond (i.e. C₀-alkyl) or an alkylenelinker. Each alkyl, cycloalkyl, and cycloalkylalkyl group may beoptionally substituted as provided for herein.

The terms “alkoxy”, “phenyloxy”, “sulfonyloxy”, and “carbonyloxy” referto an alkyl group, phenyl group, sulfonyl group, or carbonyl group,respectively, that is bonded through an oxygen atom.

The terms “alkylthio”, “trifluoromethylthio”, “cycloalkylthio”(“cyclohexylthio”), “phenylthio”, and “furanylthio” refer to an alkylgroup, trifluoromethyl group, cycloalkyl (cyclohexyl) group, phenylgroup, or furanyl group, respectively, that is bonded through a sulfuratom.

The terms “alkylcarbonyl”, “alkoxycarbonyl”, “phenylcarbonyl”, and“phenyloxycarbonyl”, refer to an alkyl, alkoxy, phenyl, or phenyloxygroup bonded through a carbonyl moiety.

The term “alkylcarbonyloxy” refers to an alkylcarbonyl group bondedthrough an oxygen atom.

The terms “(C₁-C₆)alkylsulfinyl”, “Ph¹-(C₀-C₃)alkylsulfinyl”, and“Ar²—(C₀-C₃)alkylsulfinyl”, refer to an alkyl, Ph¹-(C₀-C₃)alkyl, orAr²—(C₀-C₃)alkyl, respectively, group bonded through a sulfinyl moiety(—SO—).

The terms “alkylsulfonyl” (t-butylsulfonyl),“(C₃-C₇)cycloalkylsulfonyl”, “phenylsulfonyl”,“Ph¹-(C₀-C₃)alkylsulfonyl”, and “Ar²—(C₀-C₃)alkylsulfonyl”, refer to analkyl (t-butyl), (C₃-C₇)cycloalkyl, phenyl, Ph¹-(C₀-C₃)alkyl, orAr²—(C₀-C₃)alkyl group bonded through a sulfonyl moiety (—SO₂—).

The term “phenylamino” refers to a phenyl group bonded through anitrogen atom.

The term “N-linked” means that the referenced moiety is linked throughits nitrogen atom, by way of illustration, but without limitation,N-linked Het¹ means the Het¹ moiety is linked through a nitrogen atom inthe ring of the Het¹ moiety, and N-linked Ar² means the Ar² moiety islinked through a nitrogen atom in the ring of the Ar² moiety.

The term “halo” refers to fluoro, chloro, bromo, or iodo. Preferred halogroups are fluoro, chloro, and bromo. More preferred halo groups arefluoro and chloro.

The term “heterocycle” is taken to mean a saturated or unsaturated 4 to7 membered ring containing from 1 to 3 heteroatoms selected fromnitrogen, oxygen and sulfur, said ring optionally being benzofused.Exemplary saturated heterocycles, for the purposes of the presentinvention, include azetidinyl, pyrrolidinyl, piperidinyl,homopiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, piperazinyl, and the like. Exemplary unsaturatedheterocycles include, but are not limited to, pyrrolyl, pyrazolyl,imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl, oxazolyl,isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,thiophenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyridazinyl, and thelike. Exemplary benzofused heterocyclic rings include, but are notlimited to, indolyl, dihydroindolyl, indazolyl, benzisoxazolyl,benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, benzoxazolyl,benzo[1,3]dioxolyl, benzothiophenyl, benzothiazolyl, quinolinyl,isoquinolinyl, benzopyranyl, dihydrobenzopyranyl, cinnolinyl,quinazolinyl and the like, all of which may be optionally substituted asprovided for herein, which also includes optionally substituted on thebenzene ring when the heterocycle is benzofused.

In one embodiment, preferred heterocycles include pyrrolidinyl,piperidinyl, homopiperidinyl, tetrahydrofuranyl, tetrahydropyranyl,pyrrolyl, pyrazolyl, imidazolyl, furanyl, isoxazolyl, 1,2,4-oxadiazolyl,thiophenyl, thiazolyl, 1,2,3-thiadiazolyl, pyridyl, pyridazinyl,indolyl, dihydroindolyl, benzimidazolyl, benzofuranyl,dihydrobenzofuranyl, benzoxazolyl, benzo[1,3]dioxolyl, benzothiophenyl,benzothiazolyl, quinolinyl, isoquinolinyl, and benzopyranyl, all ofwhich may be optionally substituted as provided for herein.

In yet another embodiment, preferred heterocycles include pyridyl,pyridazinyl, and thiophenyl.

The terms “gem-”, “geminal”, or “geminate” refer to two identicalsubstituents bonded to a common carbon atom, as for example, but withoutlimitation, gem-methyl, meaning two methyl groups bound to a commoncarbon atom, as for instance in a 3,3-dimethyltetrahydrobenzofuranylgroup. For the purposes of this application, gem-ethano means anethylene substituent wherein both carbons are bound to the same carbonatom of the substituted group to form a cyclopropyl moiety, as forexample, but without limitation, the ethano substituent on the2-phenyl-(1,1-ethano)ethylamino group below:

It is to be understood that when a basic definition of a group listsoptionally allowable substituents, and in another place that group issaid to also optionally be substituted with other recited substituents,then those other recited substituents are intended to be added to thelist of optionally allowable substituents listed in the basic definitionof the group. Conversely, if in another place that group is said to bealternatively, optionally substituted with other recited substituents,then those other recited substituents are intended to replace the listof optionally allowable substituents recited in the basic definition ofthe substituent. For example, but without limitation, Ar² has a basicdefinition that recites that any of the listed heteroaromatic groups may“optionally be substituted with 1 to 3 substituents independentlyselected from the group consisting of halo, cyano, —SCF₃, (C₁-C₆)alkyloptionally further substituted with 1 to 6 fluoro substituents, and(C₁-C₆)alkoxy optionally further substituted with 1 to 6 fluorosubstituents, and wherein pyridyl and pyridazinyl may also optionally besubstituted with (C₁-C₆)alkylamino optionally further substituted with 1to 6 fluoro substituents, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl, or(C₃-C₇)cycloalkyl(C₀-C₃)alkyl-amino.” This is to be understood to meanthat any of the listed heteroaromatic groups may optionally besubstituted with [1 to 3 substituents independently selected from thegroup consisting of halo, cyano, —SCF₃, (C₁-C₆)alkyl optionally furthersubstituted with 1 to 6 fluoro substituents, and (C₁-C₆)alkoxyoptionally further substituted with 1 to 6 fluoro substituents], andthat when Ar² is selected to be pyridyl or pyridazinyl, the list ofsubstituents selectable for the 1 to 3 substituents is expanded to alsoinclude [(C₁-C₆)alkylamino optionally further substituted with 1 to 6fluoro substituents, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl, and(C₃-C₇)cycloalkyl(C₀-C₃)alkyl-amino]. Likewise, in the definition ofR¹⁴, the terminology “wherein . . . Ar², wherein Ar² is pyridyl, thenR¹⁴ may also, optionally be substituted with phenyl-CH═CH— orphenyl-C≡C— . . . ” is understood to mean that the list of substituentsselectable for the 1 to 3 substituents optionally allowed on Ar²=pyridylis again expanded to also include [phenyl-CH═CH— or phenyl-C≡C— . . . ].Conversely, later in the definition of R⁴, the terminology “wherein whenAr² is pyridyl, the pyridyl may alternatively, optionally be substitutedwith R²⁸R²⁹N—C(O)— and optionally further substituted with one methyl,—CF₃, cyano, or —SCF₃ substituent, or with 1 to 2 halo substituents”, isunderstood to mean that when R¹⁴ is selected to be A2=pyridyl, then thelist of 1 to 3 independently selected substituents optionally allowablein the basic definition of Ar² may be superceded by “R²⁸R²⁹N—C(O)— andoptionally further substituted with one methyl, —CF₃, cyano, or —SCF₃substituent, or with 1 to 2 halo substituents.”

The term “amino protecting group” as used in this specification refersto a substituent commonly employed to block or protect the aminofunctionality while reacting other functional groups on the compound.Examples of such amino protecting groups include the formyl group, thetrityl group, the acetyl group, the trichloroacetyl group, thetrifluoroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetylgroups, carbamoyl-type blocking groups such as benzyloxycarbonyl,9-fluorenylmethoxycarbonyl (“FMOC”), t-butoxycarbonyl (t-BOC), and likeamino protecting groups. The species of amino protecting group employedis not critical so long as the derivatized amino group is stable to theconditions of subsequent reactions on other positions of the moleculeand can be removed at the appropriate point without disrupting theremainder of the molecule.

The selection and use (addition and subsequent removal) of aminoprotecting groups is well known within the ordinary skill of the art.Further examples of groups referred to by the above terms are describedby T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, 3^(rd) edition, John Wiley and Sons, New York, N.Y., 1999,chapter 7, hereafter referred to as “Greene”.

The term “pharmaceutical” or “pharmaceutically acceptable” when usedherein as an adjective, means substantially non-toxic and substantiallynon-deleterious to the recipient.

By “pharmaceutical composition” it is further meant that the carrier,solvent, excipients and/or salt must be compatible with the activeingredient of the composition (e.g. a compound of Formula I). It isunderstood by those of ordinary skill in this art that the terms“pharmaceutical formulation” and “pharmaceutical composition” aregenerally interchangeable, and they are so used for the purposes of thisapplication.

The term “effective amount” means an amount of a compound of Formula Iwhich is capable of activating 5-HT_(2C) receptors and/or elicit a givenpharmacological effect.

The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction.

It is understood that compounds of the present invention may exist asstereoisomers. As such, all enantiomers, diastereomers, and mixturesthereof, are included within the scope of the present invention. Wherespecific stereochemistries are identified in this application, theCahn-Prelog-Ingold designations of (R)- and (S)- and the cis and transdesignation of relative stereochemistry are used to refer to specificisomers and relative stereochemistry. Known optical rotations aredesignated by (+) and (−) for dextrorotatary and levorotatary,respectively. Where a chiral compound is resolved into its isomers, butabsolute configurations or optical rotations are not determined, theisomers are arbitrarily designated as isomer 1, isomer 2, etc. While allenantiomers, diastereomers, and mixtures thereof, are contemplatedwithin the present invention, preferred embodiments are singleenantiomers and single diastereomers.

It is generally understood by those skilled in this art, that compoundsintended for use in pharmaceutical compositions are routinely, thoughnot necessarily, converted to a salt form in efforts to optimize suchcharacteristics as the handling properties, stability, pharmacokinetic,and/or bioavailability, etc. Methods for converting a compound to agiven salt form are well known in the art (see for example, Berge, S. M,Bighley, L. D., and Monkhouse, D. C., J. Pharm. Sci., 66:1, (1977)). Inthat the compounds of the present invention are amines and thereforebasic in nature, they readily react with a wide variety ofpharmaceutically acceptable organic and inorganic acids to formpharmaceutically acceptable acid addition salts therewith. Such saltsare also embodiments of this invention.

Typical inorganic acids used to form such salts include hydrochloric,hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric,metaphosphoric, pyrophosphoric acid, and the like. Salts derived fromorganic acids, such as aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids,aromatic acids, aliphatic and aromatic sulfonic acids, may also be used.Such pharmaceutically acceptable salts thus include chloride, bromide,iodide, nitrate, acetate, phenylacetate, trifluoroacetate, acrylate,ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, methylbenzoate, o-acetoxybenzoate, isobutyrate,phenylbutyrate, α-hydroxybutyrate, butyne-1,4-dicarboxylate,hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, citrate,formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate,maleate, hydroxymaleate, malonate, mandelate, nicotinate, isonicotinate,oxalate, phthalate, terephthalate, propiolate, propionate,phenylpropionate, salicylate, sebacate, succinate, suberate,benzenesulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate,ethylsulfonate, 2-hydroxyethylsulfonate, methylsulfonate (mesylate),naphthalene-1-sulfonate, naphthalene-2-sulfonate,naphthalene-1,5-sulfonate, p-toluenesulfonate, xylenesulfonate,tartrate, and the like.

It is well known that such compounds can form salts in various molarratios with the acid to provide, for example, the hemi-acid, mono-acid,di-acid salt, etc. Where in the salt formation procedure, the acid isadded in a specific stoichiometric ratio, unless otherwise analyzed toconfirm, the salt is presumed, but not known, to form in that molarratio. Terms such as “(acid)_(x)” are understood to mean that the molarratio of the salt formed is not known and can not be presumed, as forexample, but without limitation, (HCl) and (methanesulfonic acid)_(x).

Abbreviations used herein are defined as follows:

-   -   “2B-3 ethanol” means ethanol denatured with toluene.    -   “AIBN” means 2,2′-azobisisobutyronitrile.    -   “Anal. Calc'd” or “Anal. Calcd” means calculated elemental        analysis.    -   “APCI” means atmospheric pressure chemical ionization.    -   “bp” means boiling point.    -   “BINAP” means rac-2,2′-bis(diphenylphosphino)-1,1′binaphthyl.    -   “Boc” or “t-Boc” means tert-butoxycarbonyl.    -   “Brine” means a saturated aqueous sodium chloride solution.    -   “CV” means calorific value of oxygen.    -   “DBU” means 1,8-diazabicyclo[5.4.0]undec-7-ene.    -   “DCE” means 1,2-dichloroethane.    -   “DCM” means dichloromethane (i.e. methylene chloride, CH₂Cl₂).    -   “DIBAL-H” means diisobutylaluminum hydride.    -   “DIEA” means N,N-diisopropylethylamine.    -   “DMAP” means 4-(dimethylamino)pyridine.    -   “DME” means 1,2-dimethoxyethane.    -   “DMEA” means N,N-dimethylethylamine.    -   “DMF” means N,N-dimethylformamide.    -   “DMSO” means dimethylsulfoxide.    -   “DOI” means        (±)-1-(2,5-dimethoxy-4-[¹²⁵I]-iodophenyl)-2-aminopropane.    -   “EDC” means 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide        hydrochloride.    -   “EDTA” means ethylenediaminetetraacetic acid.    -   “EE” means energy expenditure.    -   “EtOAc” means ethyl acetate.    -   “GC-MS” means gas chromatography—mass spectrometry.    -   “GDP” means guanosine diphosphate.    -   “GTP” means guanosine triphosphate.    -   “GTPγ[³⁵S]” means guanosine triphosphate having the terminal        phosphate substituted with ³⁵S in place of an oxygen.    -   “HATU” means        O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate.    -   “HMPA” means hexamethylphosphoramide.    -   “HOBT” means 1-hydroxybenzotriazole hydrate.    -   “HPLC” means high-pressure liquid chromatography.    -   “HRMS” means high-resolution mass spectrometry.    -   “ISPA” means immunoadsorption scintillation proximity assay.    -   “m-CPBA” means meta-chloroperoxybenzoic acid.    -   “mp” means melting point.    -   “Ms” in a chemical structure means the methanesulfonyl moiety        (—SO₂CH₃).    -   “MS (ES+)” means mass spectroscopy using electrospray        ionization.    -   “MTBE” means methyl t-butyl ether.    -   “NBS” means N-bromosuccinimide.    -   “NMP” means 1-methyl-2-pyrrolidinone.    -   “NMR” means nuclear magnetic resonance.    -   “Pd/C” means palladium on activated carbon.    -   “RQ” means respiratory quotient.    -   “SCX chromatography” means chromatography on an SCX column or        cartridge.    -   “SCX column” or “SCX cartridge”, as used herein, refers to a        Varian Bond Elute® silica based strong cation exchange resin        column or disposable cartridge or equivalent.

“Sudan III” means 1-[(4-phenylazo)phenylazo]-2-naphthalenol.

“Tf” in a chemical structure means the trifluoromethanesulfonyl moiety(—SO₂CF₃).

“TFA” means trifluoroacetic acid.

“THF” means tetrahydrofuran.

“TLC” means thin layer chromatography.

While all of the compounds of the present invention are useful as5-HT_(2C) agonists, certain classes are preferred, as for example,compounds having any of the following enumerated selections ofsubstituents: Compounds wherein

-   -   1) R⁷ is halo;    -   2) R⁷ is chloro;    -   3) R⁷ is (C₁-C₆)alkyl optionally substituted with 1 to 6 fluoro        substituents;    -   4) R⁷ is (C₁-C₃)alkyl optionally substituted with 1 to 6 fluoro        substituents;    -   5) R⁷ is —CF₃;    -   6) R⁷ is (C₃-C₆)alkenyl optionally substituted with 1 to 6        fluoro substituents;    -   7) R⁷ is (C₃-C₆)alkenyl;    -   8) R⁷ is cyano;    -   9) R¹⁻⁵ are each hydrogen;    -   10) R⁴ is methyl or ethyl;    -   11) R⁴ is methyl;    -   12) R³ is methyl;    -   13) R⁸ is hydrogen;    -   14) R⁹ is (C₁-C₃)alkoxy;    -   15) R⁹ is methoxy;    -   16) R⁹ is halo;    -   17) R⁹ is chloro;    -   18) R⁶ is —C≡C—R¹⁰;    -   19) R¹⁰ is Ph¹-(C₀-C₃)alkyl;    -   20) R¹⁰ is Ph¹-(C₁-C₂)alkyl;    -   21) R¹⁰ is Phenyl(C₀-C₃)alkyl;    -   22) R¹⁰ is (C₃-C₇)cycloalkyl(C₀-C₃)alkyl;    -   23) R¹⁰ is (C₃-C₇)cycloalkylmethyl;    -   24) R¹⁰ is (C₄-C₆)alkyl;    -   25) R¹⁰ is branched (C₄-C₆)alkyl;    -   26) R¹⁰ is (C₁-C₆)alkyl substituted with 2-6 fluoro        substituents;    -   27) R¹⁰ is Ar¹—(C₀-C₃)alkyl;    -   28) R¹⁰ is Ar¹—(C₁-C₂)alkyl;    -   29) R⁶ is —O—R¹²;    -   30) R¹² is Ph²-(C₀-C₃)alkyl;    -   31) R¹² is Ph²-(C₁-C₂)alkyl;    -   32) R¹² is Ph²-(C₁-C₂)alkyl and Ph² is substituted with 1-3 halo        substituents;    -   33) R¹² is Ph²-(C₁-C₂)alkyl and Ph² is substituted with 1-3        fluoro substituents;    -   34) R¹² is Ph²-(C₁-C₂)alkyl and Ph² is substituted with cyano;    -   35) R¹² is Ph²-(C₁-C₂)alkyl and Ph² is substituted with        R³⁰R³¹N—S(O)₂—;    -   36) R¹² is Ph²-(C₁-C₂)alkyl, Ph² is substituted with        R³⁰R³¹N—S(O)₂—, R³⁰ is (C₁-C₃)alkyl optionally further        substituted with 1-3 fluoro substituents and R³¹ is hydrogen;    -   37) R¹² is Ar²—(C₀-C₃)alkyl;    -   38) R¹² is Ar²—(C₁-C₂)alkyl;    -   39) R¹² is Ar²—(C₁-C₂)alkyl and Ar² is pyridyl, thiazolyl,        oxazolyl, or pyrazolyl, each optionally substituted with methyl;    -   40) R¹² is benzazolyl-(C₁-C₃)alkyl;    -   41) R¹² is Ph²-C(O)—(C₁-C₃)alkyl,    -   42) R¹² is Ph²-C(O)—(C₁-C₃)alkyl and Ph² is substituted with 1        to 3 halo substituents;    -   43) R¹² is Ph²-C(O)—(C₁-C₃)alkyl and Ph² is substituted with 1        to 3 halofluoro substituents;    -   44) R¹² is Ph¹-S(O)—;    -   45) R¹² is (C₁-C₆)alkyl-O—C(O)—(C₃-C₆)alkyl;    -   46) R¹² is (C₁-C₃)alkyl-O—C(O)—(C₃-C₆)alkyl;    -   47) R¹² is R¹³—C(O)NH—(C₂-C₄)alkyl;    -   48) R¹² is R¹³—C(O)NH—(C₂-C₄)alkyl and R¹³ is Ph¹;    -   49) R¹² is R¹³—C(O)NH—(C₂-C₄)alkyl, R¹³ is Ph¹; substituted with        1 to 3 halo substituents;    -   50) R¹² is R¹³—C(O)NH—(C₂-C₄)alkyl and R¹³ is (C₃-C₇)cycloalkyl;    -   51) R¹² is R¹³—C(O)NH—(C₂-C₄)alkyl and R¹³ is pyridyl;    -   52) R¹² is R¹³—C(O)NH—(C₂-C₄)alkyl and R¹³ is (C₁-C₃)alkoxy;    -   53) R¹² is R¹³—C(O)NH—(C₂-C₄)alkyl and R¹³ is (C₃-C₇)cycloalkyl;    -   54) R⁶ is —S—R¹⁴;    -   55) R⁶ is —S—R¹⁴ and R¹⁴ is Ph²;    -   56) R⁶ is —S—R¹⁴, R¹⁴ is Ph² substituted with 1 to 3 halo        substituents;    -   57) R⁶ is —S—R¹⁴, R¹⁴ is Ph² substituted with cyano;    -   58) R⁶ is —S—R¹⁴, R¹⁴ is Ph²; substituted with cyano and 1 to 2        halo substituents;    -   59) R⁶ is —S—R¹⁴ and R¹⁴ is Ar²;    -   60) R⁶ is —S—R¹⁴, R¹⁴ is Ar², and Ar² is optionally substituted        pyridyl or pyridazinyl;    -   61) R⁶ is —S—R¹⁴, R¹⁴ is Ar², and Ar² is optionally substituted        thiophenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl,        1,3,4-thiadiazolyl;    -   62) R⁶ is —S—R¹⁴ and R¹⁴ is tetrahydrofuranyl or        tetrahydropyranyl;    -   63) R⁶ is —S—R¹⁴ and R¹⁴ is tetrahydrofuranyl or        tetrahydropyranyl and the tetrahydrofuranyl or tetrahydropyranyl        is substituted with oxo on a carbon adjacent to the ring oxygen;    -   64) R⁶ is —S—R¹⁴ and R¹⁴ is R⁵-L-;    -   65) L is (C₁-C₂)alkylene;    -   66) L is branched (C₂-C₃)alkylene;    -   67) L is methyl-methylene;    -   68) L is di-methyl-methylene;    -   69) L is methyl-ethylene;    -   70) L is gem-di-methyl-ethylene;    -   71) L is gem-ethano-ethylene;    -   72) R¹⁵ is Ph²;    -   73) R¹⁵ is Ph² substituted with 1 to 3 halo substituents;    -   74) R¹⁵ is Ph² substituted with cyano;    -   75) R¹⁵ is Ph² substituted with (C₁-C₆)alkoxy;    -   76) R¹⁵ is Ph² substituted with (C₁-C₆)alkoxy optionally further        substituted with 1 to 3 fluoro substituents;    -   77) R¹⁵ is Ph² substituted with (C₁-C₆)alkoxy(C₁-C₁)alkyl;    -   78) R¹⁵ is Ph² substituted with (C₁-C₆)alkoxy(C₁-C₁)alkyl        further substituted with 1 to 3 fluoro substituents;    -   79) R¹⁵ is Ph² substituted with (C₁-C₆)alkylthio;    -   80) R¹⁵ is Ph² substituted with (C₁-C₆)alkylthio optionally        further substituted with 1 to 3 fluoro substituents;    -   81) R¹⁵ is Ph² substituted with (C₁-C₆)alkylthio(C₁-C₁)alkyl;    -   82) R¹⁵ is Ph² substituted with (C₁-C₆)alkylthio(C₁-C₁)alkyl        further substituted with 1 to 3 fluoro substituents;    -   83) R¹⁵ is Ph² substituted with (C₃-C₇)cycloalkyl(C₀-C₁)alkyl;    -   84) R¹⁵ is Ph² substituted with (C₁-C₆)alkysulfonyl(C₀-C₁)alkyl        optionally further substituted with 1 to 3 fluoro substituents;    -   85) R¹⁵ is Ph² substituted with (C₁-C₆)alkylsulfinyl(C₀-C₁)alkyl        optionally further substituted with 1 to 3 fluoro substituents;    -   86) R¹⁵ is Ph² substituted with Ph¹-(C₀-C₁)alkyl-sulfonyl;    -   87) R¹⁵ is Ph² substituted with Ph¹-(C₀-C₁)alkyl;    -   88) R¹⁵ is Ph² substituted with R²⁶R²⁷N—;    -   89) R¹⁵ is Ph² substituted with Het¹;    -   90) R¹⁵ is Ph² substituted with (C₁-C₆)alkyl-C(O)— optionally        further substituted with 1 to 3 fluoro substituents;    -   91) R¹⁵ is Ph² substituted with (C₁-C₆)alkyl-C(O)— optionally        further substituted with 1 to 3 fluoro substituents;    -   92) R¹⁵ is Ph² substituted with Ph¹;    -   93) R¹⁵ is Ph² substituted with Ph¹(C₀-C₃)alkyl-O—;    -   94) R¹⁵ is Ph² substituted with Ph¹(C₀-C₃)alkyl-C(O)—;    -   95) R¹⁵ is Ph² substituted with Ph¹(C₀-C₃)alkyl-C(O)—;    -   96) R¹⁵ is Ph² substituted with Ar²(C₀-C₃)alkyl-C(O)—;    -   97) R¹⁵ is Ph² substituted with Ar²(C₀-C₃)alkyl-C(O)— and Ar² is        pyrazolyl optionally further substituted as provided for in Ar²;    -   98) R¹⁵ is Ph² substituted with R²⁸R²⁹N—C(O)—;    -   99) R¹⁵ is Ph² substituted with R²⁸R²⁹N—C(O)— and R²⁸ is        (C₁-C₆)alkyl;    -   100) R¹⁵ is Ph² substituted with R²⁸R²⁹N—C(O)— and R²⁸ is        (C₃-C₇)cycloalkyl(C₀-C₃)alkyl;    -   101) R¹⁵ is Ph² substituted with R²⁸R²⁹N—C(O)— and R²⁸ is        Ph¹-(C₀-C₂)-n-alkyl optionally substituted on the alkyl moiety        when present with (C₁-C₃)alkyl, dimethyl, or gem-ethano;    -   102) R¹⁵ is Ph² substituted with R²⁸R²⁹N—C(O)— and R²⁸ is        Ar²—(C₀-C₂)-n-alkyl optionally substituted on the alkyl moiety        when present with (C₁-C₃)alkyl, dimethyl, or gem-ethano;    -   103) R¹⁵ is Ph² substituted with Het¹-C(O)—;    -   104) R¹⁵ is Ph² substituted with Het¹-C(O)— further substituted        with Ph¹;    -   105) R¹⁵ is Ar²;    -   106) R¹⁵ is Ar² further substituted with methyl;    -   107) R¹⁵ is Ar² further substituted with        (C₃-C₇)cycloalkyl(C₀-C₂)alkyl, Het¹, pyridyl, or phenyl        optionally further substituted with methyl, —CF₃, cyano, —SCF₃,        or with 1 to 3 halo substituents;    -   108) R¹⁵ is pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl,        1,2,4-triazolyl, furanyl, oxazolyl, isoxazolyl,        1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,        thiophenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, or        1,3,4-thiadiazolyl, any of which may optionally be substituted        with 1 to 3 substituents selected from the group consisting of        halo, cyano, —SCF₃, (C₁-C₆)alkyl optionally further substituted        with 1 to 6 fluoro, and (C₁-C₆)alkoxy optionally further        substituted with 1 to 6 fluoro.    -   109) R¹⁵ is pyridyl optionally further substituted as provided        for in Ar²;    -   110) R¹⁵ is tetrahydrofuranyl or tetrahydropyranyl, either        optionally being substituted with an oxo substituent, or with        one or two groups selected independently from methyl and CF₃;    -   111) R¹⁵ is tetrahydrofuranyl or tetrahydropyranyl, being        substituted with an oxo substituent, and optionally being        further substituted with one or two groups selected        independently from methyl and CF₃;    -   112) R¹⁵-L- is pyrid-2-yl-methyl;    -   113) R¹⁵-L- is pyrid-3-yl-methyl;    -   114) R¹⁵-L- is pyrid-2-yl-CH(CH₃)—;    -   115) R¹⁵-L- is pyrid-3-yl-CH(CH₃)—;    -   116) R¹⁵ is pyridazinyl optionally further substituted as        provided for in Ar²;    -   117) R¹⁵-L- is pyridazin-2-yl-methyl;    -   118) R¹⁵-L- is pyridazin-3-yl-methyl;    -   119) R¹⁵-L- is pyridazin-2-yl-CH(CH₃)—;    -   120) R¹⁵-L- is pyridazin-3-yl-CH(CH₃)—;    -   121) R¹⁵ is pyridyl further substituted with        (C₃-C₇)cycloalkyl(C₀-C₂)alkyl, Het¹, pyridyl, or phenyl        optionally further substituted with methyl, —CF₃, cyano, —SCF₃,        or with 1 to 3 halo substituents;    -   122) R¹⁵ is pyridazinyl further substituted with        (C₃-C₇)cycloalkyl(C₀-C₂)alkyl, Het¹, pyridyl, or phenyl        optionally further substituted with methyl, —CF₃, cyano, —SCF₃,        or with 1 to 3 halo substituents;    -   123) R¹⁵ is R²²—C(O)—;    -   124) R¹⁵ is R²²—C(O)— and R² is (C₁-C₆)alkyl optionally        substituted with 1 to 6 fluoro substituents;    -   125) R¹⁵ is R²²—C(O)— and R²² is (C₁-C₆)alkoxy optionally        substituted with 1 to 6 fluoro substituents;    -   126) R¹⁵ is R²²—C(O)— and R² is (C₃-C₇)cycloalkyl(C₀-C₃)alkyl;    -   127) R¹⁵ is R²²—C(O)— and R²² is        (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-O—;    -   128) R¹⁵ is R²²—C(O)— and R²² is Ph¹-(C₀-C₃)alkyl;    -   129) R¹⁵ is R²²—C(O)— and R²² is Ph¹-(C₀-C₃)alkyl-O—;    -   130) R¹⁵ is R²²—C(O)— and R²² is Ar²—(C₀-C₃)alkyl;    -   131) R¹⁵ is R²²—C(O)— and R² is Ar²—(C₀-C₃)alkyl-O—;    -   132) R¹⁵ is R²²—C(O)— and R²² is R³²R³³N—;    -   133) R¹⁵ is phthalimido;    -   134) R¹⁵ is R¹⁷R¹⁸N—;    -   135) R¹⁵ is R¹⁷R¹⁸N— and R¹⁷ is (C₁-C₃)alkoxy-C(O)—;    -   136) R¹⁵ is R¹⁷R¹⁸N— and R¹⁷ is (C₃-C₇)cycloalkyl(C₀-C₂)—C(O)—;    -   137) R¹⁵ is R¹⁷R¹⁸N— and R¹⁷ is Ph¹-(C₀-C₂)—C(O);    -   138) R¹⁵ is R¹⁷R¹⁸N— and R¹⁷ is Ar²—(C₀-C₂)—C(O);    -   139) R¹⁵ is R¹⁶O—;    -   140) R¹⁵ is R¹⁶O— and R¹⁶ is (C₁-C₆)oalkyl-C(O)—;    -   141) R¹⁵ is R¹⁶O— and R¹⁶ is (C₃-C₇)cycloalkyl(C₀-C₂)—C(O)—;    -   142) R⁶ is R²⁴R²⁵N— and R²⁴ is (C₁-C₆)alkoxy(C₂-C₅)alkyl        optionally substituted with 1 to 6 fluoro substituents;    -   143) R⁶ is R²⁴R²⁵N— and R²⁴ is (C₁-C₆)alkylthio(C₂-C₅)alkyl        optionally substituted with 1 to 6 fluoro substituents;    -   144) R⁶ is R²⁴R²⁵N— and R²⁴ is        (C₃-C₇)cycloalkyl(C₀-C₁)alkyl-O—(C₁-C₅)alkyl;    -   145) R⁶ is R²⁴R²⁵N— and R²⁴ is        (C₃-C₇)cycloalkyl(C₀-C₁)alkyl-S—(C₁-C₅)alkyl;    -   146) R⁶ is R²⁴R²⁵N— and R²⁴ is phenyl(C₁-C₃) n-alkyl optionally        substituted on the n-alkyl moiety when present with        (C₁-C₃)alkyl, dimethyl, or gem-ethano;    -   147) R⁶ is R²⁴R²⁵N— and R²⁴ is Ph²-(C₁-C₃) n-alkyl optionally        substituted on the n-alkyl moiety when present with        (C₁-C₃)alkyl, dimethyl, or gem-ethano;    -   148) R⁶ is R²⁴R²⁵N— and R²⁴ is Ar²(C₀-C₃) n-alkyl optionally        substituted on the n-alkyl moiety when present with        (C₁-C₃)alkyl, dimethyl, or gem-ethano;    -   149) R⁶ is —R²⁴R²⁵N— and R²⁴ is Ar²(C₀-C₃) n-alkyl optionally        substituted on the n-alkyl moiety when present with        (C₁-C₃)alkyl, dimethyl, or gem-ethano, wherein Ar² contains a        nitrogen atom, and Ar² is substituted;    -   150) R⁶ is R²⁴R²¹N— and R²⁴ is Ar²(C₀-C₃) n-alkyl optionally        substituted on the n-alkyl moiety when present with        (C₁-C₃)alkyl, dimethyl, or gem-ethano, wherein Ar² contains a        nitrogen atom, and Ar² is substituted with (C₁-C₆)alkoxy        optionally further substituted with 1 to 6 fluoro,        (C₁-C₆)alkylamino optionally further substituted with 1 to 6        fluoro, or (C₃-C₇)cycloalkyl(C₀-C₂)alkyl optionally further        substituted with 1 to 6 fluoro;    -   151) R⁶ is R²⁴R²⁵N— and R²⁴ is Ar²(C₁-C₃) n-alkyl optionally        substituted on the n-alkyl moiety when present with        (C₁-C₃)alkyl, dimethyl, or gem-ethano, and wherein Ar² is        pyridyl or pyridazinyl and is substituted with (C₁-C₆)alkoxy        optionally further substituted with 1 to 6 fluoro,        (C₁-C₆)alkylamino optionally further substituted with 1 to 6        fluoro, or (C₃-C₇)cycloalkyl(C₀-C₂)alkyl optionally further        substituted with 1 to 6 fluoro;    -   152) R⁶ is R²⁴R²⁵N— and R²⁴ is Ar²(C₀-C₃) n-alkyl optionally        substituted on the n-alkyl moiety when present with        (C₁-C₃)alkyl, dimethyl, or gem-ethano, and wherein Ar² is        pyridyl substituted with R²⁸R²⁹N—C(O)— and R²⁸ is        (C₃-C₇)cycloalkyl(C₀-C₂)alkyl or Ph¹ and R²⁹ is hydrogen;    -   153) R⁶ is R²⁴R²⁵N— and R²⁴ is Ar²(C₀-C₃) n-alkyl, wherein Ar²        is pyridyl substituted with R²⁸R²⁹N—C(O)— and R²⁸ is        (C₃-C₇)cycloalkyl or phenyl optionally substituted with 1 to 3        halo, preferably fluoro, and R²⁹ is hydrogen;    -   154) R⁶ is R²⁴R²⁵N— and R²⁴ is Ph¹-(C₀-C₁)alkyl-O—(C₁-C₅)alkyl;    -   155) R⁶ is R²⁴R²⁵N— and R²⁴ is Ph¹-(C₀-C₁)alkyl-S—(C₁-C₅)alkyl;    -   156) R⁶ is R²⁴R²⁵N— and R²⁴ is        Ph¹-(C₀-C₁)alkyl-C(O)NH—(C₂-C₄)alkyl,    -   157) R⁶ is R²⁴R²⁵N— and R²⁴ is        Ph¹-(C₀-C₁)alkyl-NH—C(O)NH—(C₂-C₄)alkyl;    -   158) R⁶ is R²⁴R²⁵N— and R²⁴ is        pyridyl-(C₀-C₁)alkyl-C(O)NH—(C₂-C₄)alkyl optionally substituted        on the pyridyl moiety with methyl, —CF₃, or 1 to 3 halo        substituents;    -   159) R⁶ is R²⁴R²⁵N— and R²⁴ is        pyridyl-(C₀-C₁)alkyl-NH—C(O)NH—(C₂-C₄)alkyl optionally        substituted on the pyridyl moiety with methyl, —CF₃, or 1 to 3        halo substituents;    -   160) R⁶ is R²⁴R²⁵N— and R²⁴ is Ar³(C₁-C₂)alkyl;    -   161) R⁶ is R²⁴R²⁵N— and R²⁴ is Ar³-methyl;

It will be understood that the above classes may be combined to formadditional preferred classes. Exemplary combinations include, but arenot limited to:

-   -   162) Any one of preferred embodiments 19) through 161) (the        preferred selections for R⁶), combined with any one of preferred        embodiments 1) through 9) (the preferred selections for R⁷);    -   163) Any one of preferred embodiments 19) through 161) (the        preferred selections for R⁶), wherein R⁷ is halogen;    -   164) Any one of preferred embodiments 19) through 161) (the        preferred selections for R⁶), wherein R⁷ is chloro;    -   165) A preferred combination according to 162), 163), or 164),        wherein R¹⁻⁵, and R⁸ are each hydrogen;    -   166) A preferred combination according to 162), 163), or 164),        wherein R¹⁻⁵, R⁸ and R⁹, are each hydrogen.    -   167) Any one of preferred embodiments 37), 38), or 39), wherein        R⁷ is other than hydrogen;    -   168) Any one of preferred embodiments 37), 38), or 39), wherein        R⁹ is hydrogen;    -   169) Any one of preferred embodiments 37), 38), or 39), wherein        R⁷ is other than hydrogen and R⁹ is hydrogen;    -   170) Any one of preferred embodiments 37), 38), or 39), wherein        R⁷ is chloro and R⁹ is hydrogen;    -   171) compounds of formula (I) wherein R⁶ is —C═C—R¹⁰ and wherein        R¹⁰ is selected from the values defined in any one of        embodiments 19) to 28);    -   172) compounds of formula (I) wherein R⁶ is —O—R¹² and wherein        R¹² is selected from the values defined in any one of        embodiments 30) to 53);    -   173) compounds of formula (I) wherein R⁶ is —S—R¹⁴ and wherein        R¹⁴ is selected from the values defined in any one of        embodiments 55) to 63) or 64) wherein L is selected from the        values of 65) to 71) and R¹⁵ is selected from the values defined        in any one of embodiments 72) to 141);    -   174) compounds of formula (I) wherein R⁶ is R²⁴R²⁵N— and wherein        R²⁴ is selected from the values defined in any one of        embodiments 142) to 161);    -   175) compounds according to embodiment 172) wherein R¹² is        selected from the values defined in any one of embodiments        37), 38) or 39);    -   176) compounds of formula (I) wherein R⁷ is other than hydrogen;    -   177) compounds according to any one of embodiments 171) or 174)        wherein R⁷ is other than hydrogen;    -   178) compounds according to any one of embodiments 171) or 174)        wherein R⁷ is chloro;    -   179) compounds according to any one of embodiments 171) or 174)        wherein R⁹ is hydrogen;    -   180) compounds according to any one of embodiments 171) or 174)        wherein R⁹ is (C₁-C₃)alkoxy;    -   181) compounds according to any one of embodiments 171) or 174)        wherein R⁹ is methoxy;    -   182) compounds according to any one of embodiments 171) or 174)        wherein R⁷ is chloro and R⁹ is hydrogen;    -   183) compounds according to any one of embodiments 171) or 174)        wherein R⁷ is chloro and R⁹ is (C₁-C₃)alkoxy;    -   184) compounds according to any one of embodiments 171) or 174)        wherein R⁷ is chloro and R⁹ is methoxy;    -   185) compounds according to any one of embodiments 171) or 185)        wherein R⁹ is hydrogen;    -   186) compounds according to any one of embodiments 171) or 185)        wherein R⁹ is (C₁-C₃)alkoxy;    -   187) compounds according to any one of embodiments 171) or 185)        wherein R⁹ is methoxy;    -   188) compounds according to any one of embodiments 171) or 187)        wherein R¹⁻⁵ are each hydrogen;

Generally, when R⁶ is —S—R¹⁴, then R¹⁵-L- is the more preferred R¹⁴.When R¹⁴ or R¹⁵ is substituted Ar², para-substitution is preferred. WhenL is present, particularly preferred are methylene, andmethyl-methylene. Particularly preferred R¹⁵-L- is when R¹⁵ is Ph² and Lis methylene. Also particularly preferred is when R¹⁵ is Ph² and L ismethyl-methylene. Also particularly preferred is when R¹⁵ is Ar² and Lis methylene. Also particularly preferred is when R¹⁵ is Ar² and L ismethyl-methylene.

Also generally, when R⁶ is —NR²⁴R²⁵, then Ph²-(C₁-C₃)-n-alkyl isparticularly preferred over phenyl(C₁-C₃)-n-alkyl.

Preferred compounds of formula (I) are those wherein

-   -   R⁶ is —C≡C—R¹⁰ and wherein R¹⁰ is selected from the values        defined in any one of embodiments 19) to 28); or    -   R⁶ is —O—R¹² and wherein R¹² is selected from the values defined        in any one of embodiments 30) to 53); or    -   R⁶ is —S—R¹⁴ and wherein R¹⁴ is selected from the values defined        in any one of embodiments 55) to 63) or embodiment 64) wherein L        is selected from the values defined in any one of        embodiments 65) to 71) and R¹⁵ is selected from the values        defined in any one of embodiments 72) to 111) and 121 to 141),        or R¹⁵-L- is selected from the values defined in any one of        embodiments 112) to 120); or    -   R⁶ is R²⁴R²⁵N— and wherein R²⁴ is selected from the values        defined in any one of embodiments 143) to 161).

Particularly preferred compounds of formula (I) are those wherein R⁶ is—O—R¹² and wherein R¹² is selected from the values defined in any one ofembodiments 37), 38) or 39).

Further preferred compounds of formula (I) are those wherein R⁷ is otherthan hydrogen. In particular, R⁷ is preferably selected from the valuesdefined in any one of embodiments 1) to 8). More preferably, R⁷ isselected from halo (especially chloro), (C₁-C₃)alkyl optionallysubstituted with 1 to 6 fluoro substituents (especially methyl, ethyl,n-propyl or CF₃), and cyano.

Particularly preferred compounds of formula (I) are those wherein R⁷ ishalogen, and in particular wherein R⁷ is chloro.

Preferred compounds of formula (I) are those wherein R⁹ is(C₁-C₃)alkoxy, preferably methoxy, or halo, preferably chloro.

Also preferred are those compounds of formula (I) wherein R⁹ ishydrogen.

Particularly preferred compounds of formula (I) are those wherein R⁷ isother than hydrogen and R⁹ is hydrogen, and most especially wherein R⁷is chloro and R⁹ is hydrogen.

Further preferred compounds of formula (I) are those wherein R¹ ishydrogen.

Also preferred are those compounds of formula (I) wherein R² ishydrogen.

Also preferred are those compounds of formula (I) wherein R³ is hydrogenor methyl, and especially wherein R³ is hydrogen.

Another preferred class of compounds of formula (I) is that wherein R⁴is hydrogen, methyl or ethyl, particularly wherein R⁴ is hydrogen ormethyl, and especially wherein R⁴ is hydrogen.

Further preferred are those compounds of formula wherein R⁵ is hydrogen.

Also preferred are those compounds of formula (I) wherein R⁸ ishydrogen.

One favored group of compounds of the present invention is thatrepresented by formula (Ia), and pharmaceutically acceptable saltsthereof:

wherein

-   -   R^(7a) is halogen, and especially chloro;    -   R^(9a) is hydrogen, halogen or (C₁-C₃)alkoxy, particularly        hydrogen, chloro or methoxy, and especially hydrogen; and    -   R⁶ is as defined in relation to formula (I).

Specific preferred compounds of the present invention are thosedescribed in the Examples herein, including the free bases and thepharmaceutically acceptable salts thereof.

It will be appreciated that the preferred definitions of the varioussubstituents recited herein may be taken alone or in combination and,unless otherwise stated, apply to the generic formula (I) for compoundsof the present invention, as well as to the preferred class of compoundsrepresented by formula (Ia).

The compounds of the invention can be prepared according to thefollowing synthetic schemes by methods well known and appreciated in theart. Suitable reaction conditions for the steps of these schemes arewell known in the art and appropriate substitutions of solvents andco-reagents are within the skill of the art. Likewise, it will beappreciated by those skilled in the art that synthetic intermediates mayby isolated and/or purified by various well known techniques as neededor desired, and that frequently, it will be possible to use variousintermediates directly in subsequent synthetic steps with little or nopurification. Furthermore, the skilled artisan will appreciate that insome circumstances, the order in which moieties are introduced is notcritical. The particular order of steps required to produce thecompounds of Formula I is dependent upon the particular compound beingsynthesized, the starting compound, and the relative liability of thesubstituted moieties as is well appreciated by those of ordinary skillin the art. All substituents, unless otherwise indicated, are aspreviously defined, and all reagents are well known and appreciated inthe art.

Compounds of Formula I where R⁶ is an acetylene-linked substituent maybe prepared as illustrated in Scheme I where Pg is a suitable protectinggroup for a secondary amine such as, but not limited to,2,2,2-trifluoroacetyl or tert-butoxycarbonyl, and variables R¹, R², R⁴,R⁵, R⁷, R⁸, R⁹ and R¹⁰ are as previously defined.

Mix the 6-triflate of the 2,3,4,5-tetrahydro-1H-benzo[d]azepines (a)with an appropriately substituted acetylene, a suitable palladium/coppercatalyst mixture in a solvent, typically DMF, using triethylamine asbase, and heat to afford the desired compound (b). Deprotection reactionand the standard extractive and chromatographic techniques afford thedesired compound (Ia).

The appropriate 6-triflate of 2,3,4,5-tetrahydro-1H-benzo[d]azepines (a)may be prepared as described in Scheme II. Compound (a) may be preparedfrom 1-naphthol. 1-Naphthol can be converted to5-hydroxy-1,4-dihydronaphthalene (c) by Birch reduction using ammoniaand lithium metal at low temperature. Methylation of the 6-hydroxy groupaffords the compound (d). Ozonolysis of (d) and subsequent reductionwith sodium borohydride provide the diol (e). After converting the twohydroxyl groups into two good leaving groups, for examplemethanesulfonates, cyclize the compound (f) to the6-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepines (g) with aqueousammonia under pressure. Protect the ring nitrogen with a variety ofalkyl halides, acid chlorides or anhydrides such as trifluoroaceticanhydride to give compound (h). Subsequently convert the methyl ether(h) to the phenol (i) with BBr₃ in dichloromethane or other methods wellknown in the literature [see for example, Greene and Wuts, ProtectiveGroups in Organic Synthesis, 3rd Ed., John Wiley and sons, Chapter III,New York (1999)].

Functionalization of the aromatic ring to introduce substituents R⁷, R⁸and R⁹ are well known in the art and very depending on the substitutiondesired. Subsequent trifluoromethanesulfonylation of the 6-hydroxy (j)affords the desired 2,3,4,5-tetrahydro-1H-benzo[d]azepines (a).

Alternately, compound (g) could be prepared from1,2-bis(cyanomethyl)-3-methoxybenzene (1), previously described in theliterature (J. Med. Chem. 1984, 27, 918-921), as shown in Scheme IIIbelow.

Compounds of Formula I where R⁶ is an oxygen-linked substituent may beprepared as illustrated in Scheme IV where Pg is a suitable protectinggroup for secondary amine, such as 2,2,2-trifluoroacetyl ortert-butoxycarbonyl, and variables R⁷, R⁹ and R¹² are as previouslydefined.

Compound (m) can be prepared by treating6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepines (j) with an appropriatealkylation reagent, such as an alkyl halide or sulfonate, and a base ina suitable solvent, typically acetone, ethanol or acetonitrile, followedby he standard extractive and chromatographic techniques. Deprotectionof the ring nitrogen gives the compound (Ib). Alternately, compound (m)can be obtained by Mitsunobu reaction with an appropriate alcohol, aphosphine reagent such as triphenylphosphine, and diethylazodicarboxylate (DEAD) or 1,1′-(azodicarbonyl)-dipiperidine in ananhydrous solvent, for example THF.

Compounds of Formula Ic where R⁶ is a nitrogen-linked substituent may beprepared as illustrated in the Scheme V. The 6-triflate protected2,3,4,5-tetrahydro-1H-benzo[d]azepines (a) can be converted to thecompounds (n), under Buchwald conditions, by treatment with anappropriate amine (q) in the presence of an effective palladiumcatalyst, and a base in a suitable solvent, typically toluene or1,4-dioxane under an inert atmosphere. Introduction of a secondsubstituent R²⁵, if needed, may be performed. Standard work-up andchromatographic techniques followed by deprotection, give the compound(Ic).

Alternately 6-amino-2,3,4,5-tetrahydro-1H-benzo[d]azepines (p) can betransformed to the desired compounds (n) by reaction with an appropriatebromide (r), and an appropriate base in a suitable solvent.

Bromides (r) are either commercially available or may be prepared bymethods well known to the skilled artisan. Amines (q) are eithercommercially available or may be prepared by methods well known to theskilled artisan.

Compounds of Formula I where the R⁶ is a sulfur-linked substituent maybe prepared as illustrated in the Scheme VI.

Heat the appropriately substituted3-(tert-butoxycarbonyl-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(s) with an appropriate base in a suitable solvent, such as methanol, toobtain the intermediate thiol (t). Isolate the intermediate thiol (t),if required, and treat it with an appropriate electrophile (halide oralkyl sulfonate). Isolate the compound (u) by standard extractive andchromatographic techniques and deprotect to afford the desired compound(Id).

The requisite halides or alkyl sulfonates are either commerciallyavailable or may be prepared by methods well known to the skilledartisan.

The skilled artisan will also appreciate that not all of thesubstituents in the compounds of Formula I will tolerate certainreaction conditions employed to synthesize the compounds. These moietiesmay be introduced at a convenient point in the synthesis, or may beprotected and then deprotected as necessary or desired, as is well knownin the art. The skilled artisan will appreciate that the protectinggroups may be removed at any convenient point in the synthesis of thecompounds of the present invention. Methods for introducing and removingprotecting groups used in this invention are well known in the art; see,for example, Greene and Wuts, Protective Groups in Organic Synthesis,3^(rd) Ed., John Wiley and sons, New York (1999).

The following Preparations and Examples are illustrative of methodsuseful for the synthesis of the compounds of the present invention.Exemplified compounds are also particularly preferred compounds of thepresent invention.

General Procedure 1-1

Dissolve the appropriately substituted3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine inammonia/methanol solution (1.0-7.0 M). Stir for 1-16 h at ambienttemperature unless otherwise specified. Remove the volatiles in vacuo.Purify by chromatography on silica gel eluting with 1-20% 2Mammonia/methanol in DCM, or by SCX chromatography eluting with 1.0-7.0 Mammonia in methanol.

General Procedure 1-2

Dissolve the appropriately substituted3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.0equiv.) in methanol. Add a 0.5 M aqueous solution of potassium carbonate(4.0 equiv.) and stir at ambient temperature for 6 h. Concentrate invacuo and partition the residue between water and DCM. Extract theaqueous phase twice with DCM. Dry the combined organic extracts overNa₂SO₄, filter and concentrate in vacuo. If needed, purify bychromatography on silica gel eluting with 1-20% 2M ammonia/methanol inDCM, or by SCX chromatography eluting with 1.0-7.0 M ammonia inmethanol.

General Procedure 1-3

Dissolve the appropriately substituted3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.0equiv.) in methanol or ethanol (0.1 to 2M solution) and add from 10-50%by volume of a 1.0-5.0 N aqueous solution of sodium hydroxide or lithiumhydroxide. Stir the reaction mixture at ambient temperature for 0.25-16h and concentrate in vacuo. Partition the residue between EtOAc or DCMand water. Separate and dry the organic fraction over Na₂SO₄, filter,and concentrate in vacuo. Purify by SCX chromatography, followed bychromatography on silica gel eluting with 1-20% 2M ammonia/methanol inDCM or reverse phase HPLC.

General Procedure 1-4

Dissolve the appropriately substituted3-tert-butoxycarbonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine in 4Mhydrogen chloride in dioxane or 1M hydrogen chloride in ethyl ether andstir the mixture for 2-16 h at ambient temperature unless otherwisespecified. Remove the solvent in vacuo. If a solid is obtained, wash thesolid with ether and filter under vacuum to afford the desiredhydrochloride salt. If an oil is obtained, dissolve the oil in theminimal volume of DCM, methanol or EtOAc and add ether to precipitateout the solid. Remove the solvent in vacuo, wash the solid with etherand filter. Dry the solid in vacuo or under a stream of nitrogen.

General Procedure 1-5

Dissolve the appropriately substituted3-tert-butoxycarbonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine in a mixtureof trifluoroacetic acid/DCM (from 1:0 to 1:10 ratio) and stir thereaction for 1-16 h at ambient temperature. Concentrate in vacuo andeither subject the residue to SCX chromatography or partition theresidue between saturated aqueous NaHCO₃ and DCM or EtOAc. Dry theorganic layer over Na₂SO₄ and concentrate in vacuo. Purify by eitherchromatography on silica gel (eluting with 1-20% 2M ammonia/methanol inDCM) or reverse phase HPLC.

General Procedure 1-6

Add acetyl chloride (40 equiv.) to cold methanol (0° C.) and stir for 5min. Then add a solution of the appropriately substituted7-chloro-3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1 equiv.) in methanol. Stir the reaction at ambient temperature for 12h. Remove the solvent in vacuo, basify with saturated aqueous NaHCO₃ andextract three times with DCM. Dry the combined organic extracts overNa₂SO₄, filter and concentrate in vacuo. Purify by chromatography onsilica gel, eluting with 1-20% 2M ammonia/methanol in DCM.

General Procedure 2-1

Dissolve the purified free base (1 equiv.) in acetone, ether or methanoland add a solution of succinic acid (1 equiv.) in a minimal volume ofacetone or methanol. Stir for 1 h at ambient temperature. Concentrate toan oil, add a minimal volume of DCM and ethyl ether to precipitate outthe salt. Alternatively, to precipitate out the salt, allow the reactionmixture to stand 1-16 h at ambient temperature, 4° C. or −10° C. and addether or hexane. Filter and wash the solid with ether or hexane toobtain the succinate salt. Alternatively, evaporate the solvent invacuo, wash the solid with ether and filter or decant the solvent toobtain the succinate as a solid. Dry the solid in vacuo or under astream of nitrogen.

General Procedure 2-2

Dissolve the purified free base (1 equiv.) in a minimal volume ofacetone, dioxane, methanol or DCM and add an excess of 4M hydrogenchloride in dioxane or a 1M solution of hydrogen chloride in ethylether. Stir for 1 h and evaporate the solvent to obtain the salt as asolid. Alternatively, allow the reaction mixture to stand 1 to 16 h atambient temperature and add ether or hexane to precipitate out the salt.Filter and wash the solid with ether or hexane to obtain the salt as asolid. Alternatively, evaporate the solvent in vacuo, wash the solidwith ether, filter or decant the solvent to obtain the hydrochloridesalt as a solid. Dry the solid in vacuo or under a stream of nitrogen.

General Procedure 2-3

Dissolve the purified free base in methanol, add a solution of ammoniumchloride (1 equiv.) in methanol and stir for 1 h. Slowly remove thevolatiles in vacuo. Dissolve the residue in methanol and remove most ofthe solvent in vacuo. Add anhydrous ethyl ether or EtOAc to precipitateout the hydrochloride salt. Collect the solid, wash the solid with etherand then dry the solid in vacuo or under a stream of nitrogen.

General Procedure 2-4

Dissolve the purified free base (1.0 equiv.) in methanol. Add a 0.5 Msolution of methanesulfonic acid in methanol (2.0 equiv). Mix well, stirfor 1 h, then remove the solvent in vacuo. Dissolve the residue into aminimal volume of DCM. Add ethyl ether to precipitate out the solid.Remove the solvent in vacuo to form a foam. Dry in vacuo or under astream of nitrogen to obtain the methanosulfonic acid salt

General Procedure 2-5

Dissolve the purified free base (1 equiv.) in a minimal volume ofacetone and add a solution of oxalic acid (1 equiv.) in a minimal volumeof acetone. Allow the mixture to stand 10 min to 16 h at ambienttemperature to −10° C., and/or add ether or hexane to precipitate outthe solid. Filter and wash the solid with ether or hexane to obtain theoxalic acid salt as a solid. Dry the solid in vacuo or under a stream ofnitrogen.

General Procedure 2-6

Dissolve the purified free base (1 equiv.) in a minimal volume ofcyclohexane, isohexane, chloroform, dichloromethane, methanol or amixture thereof and add a solution of (L)-tartaric acid in isopropanolor methanol. If a solid precipitate out, filter and wash the solid withether, cyclohexane, isohexane or EtOAc. If no solid formation isobserved, remove all the volatiles in vacuo to form a foam. Dry in vacuoor under a stream of nitrogen to obtain the tartaric acid salt.

General Procedure 3

Dissolve the appropriately substituted3-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineor7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1 equiv.), PdCl₂(PPh₃)₂ (0.1 equiv.), tetrabutyl ammonium iodide (3equiv.), and copper(I) iodide (0.3 equiv.) in triethylamine/DMF (1:5).Stir the mixture for 5 min at ambient temperature, add the appropriatelysubstituted acetylene (2 equiv.) and heat at 70° C. for 2-16 h in asealed tube. Cool the reaction mixture to ambient temperature, dilutewith EtOAc/hexane (1:1) and wash with water. Dry the organic fractionover Na₂SO₄, filter and concentrate in vacuo. Purify by chromatographyon silica gel eluting with hexane/EtOAc mixtures.

Preparation 17-Chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine

5-Methoxy-1,4-dihydronaphthalene: Add powdered potassium carbonate(193.1 g, 1.397 mol) to a solution of 5-hydroxy-1,4-dihydronaphthalene[68.08 g, 90% potency based on ¹H-NMR, 0.4657 mol, from Societa ItalianaMedicinala Scandicci, s.r.l., Reggello (Firenze), Italy] in ethanol (700mL). Cool the solution to 0° C. with ice/water and add dimethyl sulfate(88.1 g, 66.1 mL, 0.699 mol) dropwise, maintaining the temperaturebetween 5° C. and 10° C. Then heat the reaction mixture to 40° C. untilthe TLC (10:1 hexane/EtOAc) shows the absence of starting material(about 2 h). Filter off the solids by vacuum filtration and remove thesolvent in vacuo. Dilute the residual brown oil with diethyl ether (500mL), wash with 10% aqueous NH₄OH (500 mL), water (500 mL), brine (500mL), dry the organic layer over Na₂SO₄, filter and concentrate in vacuoto give the crude product as a brown oil (73 g). Purify the crudeproduct by short path distillation under vacuum (bp 120-130° C./5 Torr)to give the desired intermediate as a clear oil (69.0 g, 92.5% potencycorrected) (contains some 1,2,3,4-tetrahydro-5-methoxynaphthalene as animpurity). ¹H NMR (300 MHz, CDCl₃), 87.15 (t, 1H, J=7.9), 6.72 (dd, 2H,J=15.7, 7.9), 5.93-5.88 (m, 2H), 3.83 (s, 3H), 3.42-3.39 (m, 2H),3.30-3.28 (m, 2H); R_(f)=0.58 eluting with 10:1 hexane/EtOAc.2,3-Bis-(2-hydroxyethyl)-1-methoxybenzene: Charge a four-neck 5 L flaskequipped with an over-head mechanical stirrer, reflux condenser,thermocouple, and gas dispersion apparatus with5-methoxy-1,4-dihydronaphthalene (264.54 g, 89.5% potency based on¹H-NMR, 1.478 mol) in DCM (1.3 L) and 2B-3 ethanol (1 L). Add sudan III(10 mg) to give a faint red color. Cool the solution to −65° C. orlower, then pass O₃ through the solution until the solution turns alight yellow color and the TLC (10:1 hexane/EtOAc, KMnO₄ stain) showsthe absence of the starting material (about 30 h). Transfer the solutionvia cannula into a slurry of NaBH₄ (97.8 g, 2.59 mol) in 2B-3 ethanol(500 mL) cooled in ice/water. It is important that the temperature bemaintained at or above 0° C., as for example between 0° C. and 10° C.,throughout the transfer to ensure the ozonide is completely reduced tothe diol. After the transfer is complete, warm the solution to ambienttemperature and stir for about 30 min. Cool the slurry to 0° C. withice/water then slowly add acetone (540 mL, 7.4 mol) to remove excessNaBH₄. After all the solids dissolve, remove the solvent in vacuo.Dissolve the yellow solid in DCM (1 L) and water (1 L), separate thelayers and extract the aqueous layer with DCM (750 mL). Wash thecombined organic layers with brine (1.5 L), add toluene (750 mL) andremove the solvent in vacuo. Dissolve the solid in DCM (500 mL) withheating, then add toluene (750 mL) and concentrate the solution in vacuoto give the desired intermediate as a light yellow solid (283.7 g, 89%potency corrected, mp 82-83° C.) (contains1,2,3,4-tetrahydro-5-methoxynaphthalene as an impurity (8.6%)). Furtherpurify the product by vacuum drying overnight at 75° C., 5 Torr, toremove all but trace amount of the1,2,3,4-tetrahydro-5-methoxynaphthalene impurity. ¹H NMR (300 MHz,CDCl₃), δ 7.16 (dd, 1H, J=8.2, 7.6), 6.83 (s, 1H, J=7.0), 6.76 (s, 1H,J=8.2), 3.85-3.77 (m, 7H), 3.01-2.91 (m, 4H), 2.35 (s, 2H); ¹³C NMR (300MHz, DMSO-d₆), δ 157.5, 138.9, 126.5, 125.2, 122.0, 108.4, 62.1, 60.5,55.3, 36.1, 29.6; IR (KBr): 3006, 2960, 2886, 2829, 1583, 1461, 1440,1264, 1091, 1041 cm⁻¹; MS (ES+) m/z 178 (M+H)⁺; Anal. Calc'd forC₁₁H₁₆O₃: C, 67.32; H, 8.22; N, 0. Found: C, 67.26; H, 8.10; N, 0.21.R_(f)=0.23 eluting with 95:5 DCM/methanol.2,3-Bis-(2-methanesulfonyloxyethyl)-1-methoxybenzene: To a slurry of2,3-bis-(2-hydroxyethyl)-1-methoxybenzene (50.6 g, 0.258 mol, 1 equiv.)and triethylamine (78.3 g, 0.774 mol, 3 equiv.) in DCM (500 mL) at 0°C., add dropwise a solution of methanesulfonyl chloride (65.0 g, 0.567mol, 2.2 equiv.) in DCM (100 mL) over 45 min. The addition is exothermicand the methanesulfonyl chloride is added at a rate to keep thetemperature below 10° C. After the addition is complete, warm thereaction to ambient temperature. Wash the solution with water (2×500mL), and then brine (750 mL). Dry the organic layer over Na₂SO₄, filterand concentrate in vacuo to obtain the desired intermediate as a darkyellow oil (87.4 g, 96.2%), which is used in the next reaction withoutfurther purification. An analytical sample is obtained by flash columnchromatography eluting with 100% diethyl ether. ¹H NMR (300 MHz, CDCl₃),δ 7.20 (t, 1H, J=7.9), 6.82 (s, 1H, J=7.2), 6.80 (s, 1H, J=8.2),4.41-4.34 (m, 4H), 3.83 (s, 3H), 3.16-3.09 (m, 4H), 2.91 (s, 3H), 2.87(s, 3H); ¹³C NMR (300 MHz, CDCl₃), δ 158.07, 136.55, 128.26, 123.34,122.39, 109.24, 69.88, 69.08, 55.55, 37.35, 37.14, 32.57, 26.47; ¹³C NMR(300 MHz, DMSO-d₆), δ 157.58, 136.79, 127.81, 122.91, 122.00, 109.33,70.19, 68.88, 55.55, 36.49, 36.47, 31.56, 25.72; IR (KBr): 1586.8,1469.4, 1358.51, 1267.3, 1173.9, 1105.4, 972.4, 954.6, 914.3 cm⁻¹; MS(ES+) m/z 257 (M+H)⁺; Anal. Calc'd. for C₁₃H₂₀O₇S₂: C, 44.31; H, 5.72;N, 0. Found: C, 44.22; H, 5.68; N, 0.13. R_(f)=0.72 eluting with 95:5DCM/methanol.6-Methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine: Dissolve2,3-bis-(2-methanesulfonyloxyethyl)-1-methoxybenzene (474.4 g, 1.346mol) in acetonitrile (7 L) and split the mixture into two equal lots. Intwo separate runs, add concentrated aqueous NH₄OH (3.5 L) and charge thesolution to a pressure vessel (PARR apparatus). Heat the solution in aclosed reactor to 100° C. over 20 min (internal pressure reaches about100 psi), and maintain at 100° C. until the reaction is complete (about1 h, HPLC monitored). Cool the reaction mixture to ambient temperature.Combine the two lots and remove the solvent in vacuo. Dissolve theresidue in MTBE (3.5 L) and water (3.5 L). Adjust the pH to 6.5 using 2Maqueous NaOH or 1M aqueous HCl as appropriate (typically the pH is aboutpH=5.1 and the adjustment requires about 50 mL 2M aqueous NaOH). Discardthe organic layer, adjust the aqueous layer to pH=13 using 50% NaOH(about 150 mL). Extract with MTBE (2×3.5 L), wash the combined organiclayers with brine (3.5 L), dry over Na₂SO₄, filter and concentrate invacuo to give the title compound as a crude yellow oil that solidifiesupon standing (179.3 g). Use the material for the next step withoutfurther purification. Prepare an analytical sample by purification bytwo Kugelrohr distillations to give a clear oil that solidifies uponstanding, mp 44.3-45.0° C. ¹³C NMR (300 MHz, DMSO-d₆) □ 156.1, 144.4,130.3, 126.2, 121.5, 108.9, 55.5, 48.2, 47.9, 39.9, 29.1; MS (ES+) m/z163 (M+H)⁺; Anal. Calc'd for C₁₁H₁₅NO: C, 74.54; H, 8.53; N, 7.90.Found: C, 74.28; H, 8.62; N, 7.86.6-Methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine Hydrochloride: Dissolvecrude 6-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (35.1 g, 0.198mol) in 2B-3 ethanol (250 mL), heat the solution to reflux and add 2MHCl in ethanol (108.9 mL, 0.218 mol, 1.1 equiv.). Slowly add heptane(700 mL) over 10 min, then remove the heating mantle and cool thesolution to ambient temperature, and finally continue the cooling withan ice/water mixture. Collect the resulting solid by vacuum filtrationand wash with cold ethanol:heptane (1:2) (3×100 mL), air-dry for 15 minunder vacuum, then further dry the product in a vacuum oven at 60° C.for 1 h to give the desired intermediate as a white granular solid(35.53 g, 63%): mp 246.6-246.9° C.; ¹H NMR (300 MHz, DMSO-d₆), δ 9.82(broad s, 1H), 7.12 (dd, 1H, J=7.6, 7.9), 6.88 (d, 1H J=8.2), 6.78 (d,1H, J=7.3), 3.75 (s, 3H), 3.20-3.00 (m, 8H); ¹³C NMR (300 MHz, DMSO-d₆),δ 156.2, 141.3, 127.4, 127.2, 121.6, 109.7, 55.7, 44.9, 44.7, 31.6,21.7; MS (ES+) m/z 178 (M+H)⁺; Anal. Calc'd for C₁₁H₁₅ClNO: C, 62.12; H,7.11; N, 6.59. Found: C, 61.95; H, 7.64; N, 6.58.6-Methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:To a slurry of 6-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepinehydrochloride (35.3 g, 0.165 mol, 1 equiv.) and triethylamine (69.1 mL,0.496 mol, 3 equiv.) in DCM (300 mL) cooled at 0° C. with ice/water, adddropwise a solution of trifluoroacetic anhydride (25.7 mL, 0.182 mol,1.1 equiv.) in DCM (40 mL) over 30 min, but at a rate that maintains thetemperature below 10° C. After the addition is complete, warm thereaction mixture to ambient temperature and stir until the reaction iscomplete (verify by TLC using 9:1 CH₂Cl₂:methanol, about 2 h.). Wash thesolution with water (2×350 mL), and then brine (350 mL), dry the organiclayer over Na₂SO₄, filter and concentrate in vacuo to give desiredintermediate as a yellow oil that solidifies upon standing (44.9 g,96%). Use the material without further purification in the next step.Prepare an analytical sample by chromatography on silica gel elutingwith 40% diethyl ether in hexane, mp 74-76° C. ¹H NMR (300 MHz, CDCl₃),δ 7.16-7.11 (m, 1H), 6.81-6.74 (m, 2H), 3.81 (s, 3H), 3.79-3.64 (m, 4H),3.11-3.07 (m, 2H), 2.99-2.95 (m, 2H); ¹H NMR (300 MHz, DMSO-d₆), δ 7.13(dd, 1H, J=1.5, 7.0), 7.08 (d, 1H, J=1.5), 6.88-6.74 (m, 1H), 3.75 (s,3H), 3.67-3.61 (m, 4H), 3.04-2.92 (m, 4H); ¹³C NMR (300 MHz, DMSO-d₆), δ156.43. 156.38, 155.06, 155.00, 154.60, 154.54, 154.14, 154.08, 141.31,141.04, 127.44, 127.18, 127.05, 127.01, 122.27, 121.94, 121.90, 118.46,114.64, 110.80, 109.52, 109.41, 55.63, 55.61, 47.11, 47.07, 46.67,46.63, 45.61, 45.16, 35.90, 34.65, 26.18, 24.91; Anal. Calc'd forC₁₃H₁₄F₃NO₂: C, 57.14; H, 5.16; N, 5.13. Found: C, 57.17; H, 5.27; N,5.08.6-Hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:To a 1M solution of BBr₃ (1.1 L, 1.6 equiv.), cooled at 0° C. with anice-water bath, add6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(187 g, 0.684 mol) in DCM (200 mL) over 1 h., while maintaining thetemperature between 0° C. and 10° C. Warm the reaction mixture toambient temperature and stir until HPLC indicates completion of thereaction (about 2 h.). Cool the solution to 0° C. and transfer it viacannula into an ice/water solution (1.2 L), thereby precipitating theproduct as a white solid. Add EtOAc (2 L) to dissolve most of theprecipitate, separate the layers and concentrate the organic layer invacuo. Extract the aqueous layer three times with EtOAc (2×2 L, 1×1 L).Wash the combined organic layers with water (2 L), and then brine (2 L),dry over Na₂SO₄, filter and concentrate in vacuo to give the desiredintermediate as a light yellow solid (166.3 g, 94%). Use the product forthe next step without further purification. Prepare an analytical sampleby chromatography on silica gel eluting with 40% diethyl ether inhexane: mp 183.0-185.2° C. ¹H NMR (300 MHz, DMSO-d₆), δ 9.39 (s, 1H),6.94-6.88 (m, 1H), 6.72-6.68 (m, 1H), 6.61-6.57 (m, 1H), 3.67-3.32 (m,4H), 2.99-2.86 (m, 4H); ¹³C NMR (300 MHz, DMSO-d₆), δ 154.50, 141.47,141.18, 126.77, 126.64, 125.77, 125.33, 120.38, 120.32, 118.49, 114.67,113.64, 113.47, 47.31, 47.27, 47.00, 46.96, 45.83, 45.49, 36.17, 34.93,26.46, 25.18, 20.66, 14.00; MS (ES+) m/z 260 (M+H)⁺; Anal. Calc'd. forC₁₂H₁₂F₃NO₂: C, 55.60; H, 4.67; N, 5.40. Found: C, 55.51; H, 4.71; N,5.29.7-Chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Heat a mixture of6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(120 g, 0.4629 mol) and toluene (14.4 L) to 70° C. for 45 min until mostof the starting material is dissolved. Add diisobutylamine (1.197 g,1.62 mL, 9.26 mmol) followed by addition of sulfuryl chloride (62.48 g,37.19 mL, 0.463 mol) in toluene (360 mL) over 20 min. Stir the reactionmixture for 50 min and then add additional sulfuryl chloride (4.536 g,2.70 mL, 0.0336 mol) neat and stir the reaction mixture for 15 min at70° C. Cool the reaction mixture to 24° C. over 30 min and then add 1Nhydrochloric acid (2.00 L). Separate, wash the organic layer withsaturated aqueous NaHCO₃ (2.00 L), brine (2.00 L) and then dry overNa2SO4. Filter and remove the solvent with a rotary evaporator at 70° C.until about 672.5 g remains using the minimum effective vacuum in orderto maintain a vapor phase sufficient to prevent drying above the solventline and self-seeding, thus preventing crystallization under theseconditions. Using toluene heated to 70° C., transfer the light-yellowsolution to a preheated (70° C.) 3-neck flask equipped with a mechanicalstirrer. Lower the temperature to 58° C. over 1 h. If available, seedthe solution with crystals of7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepinefrom a prior synthesis to enhance crystallization. After 30 min, reducethe temperature further to 55° C. and observe the initiation of thecrystallization process. Hold the temperature at 55° C. for 2 h.followed by 4 h. at 45° C., then turn off the heat allowing the mixtureto slowly reach 24° C. (ambient temperature). After stirring for 8 h.with the heat off, cool the mixture to 0° C. for 2 h. followed by 2 h.at −10° C. Collect the resulting dense, white, granular crystals byvacuum filtration at −10° C. Rinse the crystals twice with cold (−10°C.) toluene and vacuum dry at 50° C., 5 Torr, for 12 h., to obtain thedesired intermediate as a white solid (120.7 g, 99.5% purity, 88.8%): mp133-134° C. MS (ES+) m/z 294 (M+H)⁺. Anal. Calc'd for C₁₂H₁₁ClF₃NO₂: C,49.08; H, 3.78; N, 4.77; Cl, 12.07. Found: C, 49.01; H, 3.63; N, 4.72;Cl, 12.32.7-Chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Cool a solution of7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(60 g, 0.204 mol), triethylamine (62.6 mL, 0.448 mol, 2.2 equiv.), andDCM (590 mL) in an ice bath and add dropwise trifluoromethanesulfonicanhydride (43.5 mL, 0.258 mol, 1.26 equiv.) over 70 min. Remove the icebath and stir the reaction mixture for 2 h Wash the reaction mixturesequentially with water (500 mL), 1N aqueous HCl (500 mL), water (500mL), and brine (560 mL). Dry the organic layer over Na₂SO₄ andconcentrate in vacuo to give the crude product as a brown solid (90 g).Dissolve the solid in warm toluene (200 mL). Further purify by plugfiltration chromatography over silica gel (500 g) eluting sequentiallywith hexane (1 L), hexane/EtOAc (9:1, 1 L), hexane/EtOAc (4:1, 1 L), andhexane/EtOAc (7:3, 9 L). Pool the eluents and evaporate the solvent toobtain the product as a yellow tan solid (86.3 g). Dissolve the solid inwarm EtOAc (86 mL) and then add hexane (700 mL). If available, seed thesolution with crystals of7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanelsulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepinefrom a prior synthesis to enhance crystallization. Allow the mixture tostand at ambient temperature for 30 min. Cool the mixture at about −10°C. for 2 h., filter, rinse the crystals with cold (−110° C.)hexane/EtOAc, and air-dry on the filter under vacuum to obtain the titlecompound as a first crop of crystals (73.54 g). Concentrate the motherliquor to obtain a solid (12.7 g). Recrystallize the solid in a mixtureof EtOAc/hexane (15 mL:211 mL) to obtain additional title compound (7.65g, total yield: 81.19 g, 93%).

Preparation 23-(2,2,2-Trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Cool a solution of6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(2 g, 7.72 mmol), triethylamine (1.4 mL, 10.1 mmol) and DCM (50 mL) in acryogenic bath set at −30° C. and add dropwise trifluoromethanesulfonicanhydride (1.7 mL, 10.1 mmol) over 20 min. Stir at −30° C. for 2 handthen warm to ambient temperature overnight. Wash the reaction mixturesequentially with water (100 mL), 1N aqueous HCl (100 mL), water (200mL), and brine (200 mL). Dry the organic layer over Na₂SO₄ andconcentrate in vacuo to give the title compound as a colorless to lightyellow oil (2.7 g, 89%) that was used without purification. Obtain ananalytical sample by chromatography on silica gel eluting withhexane/EtOAc (9:1) to give the title compound as an off-white waxysolid. GC-MS m/z: 391 (M⁺).

Preparation 33-tert-Butoxycarbonyl-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Dissolve6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(5 g, 19.3 mmol) in 7N ammonia in methanol (50 mL) and stir at ambienttemperature for 16 h. Concentrate the reaction mixture to an oil and usewithout further purification. Dissolve the residue in a solvent mixtureconsisting of methanol (20 mL), DCM (10 mL) and water (100 mL), and addpotassium carbonate (5 g) and di-tert-butyl-dicarbonate (5.05 g, 23.2mmol). Stir the reaction mixture at ambient temperature for 16 h andconcentrate in vacuo. Extract the aqueous phase with DCM, dry overNa₂SO₄, filter and concentrate. Use the residue without furtherpurification. Dissolve the material in a mixture of DCM (300 mL) andpyridine (30 mL) and cool in an ice bath. Add dropwise to the stirredsolution trifluoromethanesulfonic anhydride (5.84 mL, 34.7 mmol) andstir the reaction mixture for 2 h at ambient temperature. Dilute thereaction mixture with DCM (400 mL) and wash with 2.5N aqueous HCl. Drythe organic fraction over Na₂SO₄, filter and concentrate to give thetitle compound as a yellow solid (6.1 g, 80%). MS (ES+) m/z: 396 (M+H)⁺.

Preparation 47-Fluoro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Add N-fluoro-4,6-bis(trifluoromethyl)-pyridinium 2-sulfonate (3.02 g,9.6 mmol) to a stirred mixture of6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(2.5 g, 9.6 mmol) and hexafluoro-2-propanol (10 mL) in DCM (150 mL).Stir at ambient temperature for 16 h. Concentrate the reaction mixtureand partition the residue between EtOAc and 1N aqueous HCl. Wash theorganic fraction with saturated aqueous NaHCO₃, brine, dry over Na₂SO₄,filter and concentrate. Purify by chromatography on silica gel elutingwith hexane/EtOAc (20:1, 10:1, 6:1, 5:1 and 3:1) to give7-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a white solid (1.8 g, 68%). Dissolve7-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.5 g, 5.41 mmol) in a mixture of DCM (20 mL) and pyridine (2 mL) andcool in an ice bath. Add dropwise to the stirred solution a mixture oftrifluoromethanesulfonic anhydride (1.64 mL, 9.74 mmol) in DCM and stirthe reaction for 1.5 h at ambient temperature. Dilute the reaction withDCM (300 mL) and wash with 2.5N aqueous HCl. Dry the organic fractionover Na₂SO₄, filter and concentrate to give the title product as a whitesolid (2.2 g, 99%). MS (ES+) m/z: 410 (M+H)⁺.

Preparation 53-tert-Butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Dissolve7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(3 g, 10.2 mmol) in 7 N ammonia in methanol (50 mL) and stir at ambienttemperature for 16 h. Concentrate the reaction mixture to an oil and usewithout further purification. Dissolve the residue in a solvent mixtureconsisting of DCM (25 mL) and saturated aqueous potassium carbonatesolution (25 mL) and add di-tert-butyl-dicarbonate (2.2 g, 10.2 mmol).Stir the reaction mixture at ambient temperature for 4 h, concentrate invacuo and extract the aqueous residue with DCM. Dry the organic fractionover Na₂SO₄, filter and concentrate in vacuo. Purify by chromatographyon silica gel eluting with EtOAc/hexane (1:5) to give the title compoundas a white solid (2.3 g, 76%). MS (ES−) m/z: 296 (M−H)⁻.

EXAMPLE 1 6-(3-Phenyl-prop-1-ynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 3 to couple3-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.6 g, 1.5 mmol) with 3-phenyl-1-propyne (0.38 mL, 3 mmol). Purify bychromatography on silica gel eluting with hexane/EtOAc (1:0, 40:1 and20:1) to give3-tert-butoxycarbonyl-6-(3-phenyl-prop-1-ynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an orange oil (400 mg, 74%).

Use a method similar to the General Procedure 1-5 to deprotect3-tert-butoxycarbonyl-6-(3-phenyl-prop-1-ynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(68 mg, 0.19 mmol). Purify by chromatography on silica gel eluting withDCM/2M ammonia in methanol (1:0, 20:1 and 10:1) to obtain the free baseof the title compound. Use a method similar to the General Procedure 2-2to give the title compound as a tan solid (48 mg, 85%). MS (ES+) m/z:262 (M+H)⁺.

Examples 2-4 may be prepared essentially as described in Example 1 byusing3-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate alkyne. Overall yields and MS (ES+) data are shownin the Table below.

Yield MS (ES+) Ex. R Compound (%) m/z 2 Benzyl 6-(4-Phenyl-but-1-ynyl)-60 276 (M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Hydrochloride 3Cyclopentyl 6-(3-Cyclopentyl-prop- 73 254 (M + H)⁺ 1-ynyl)-2,3,4,5-tetrahydro-1H- benzo[d]azepine Hydrochloride 4 Cyclohexyl6-(3-Cyclohexyl-prop-1- 79 268 (M + H)⁺ ynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine Hydrochloride

EXAMPLE 56-(3,3-Dimethyl-but-1-ynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 3 to couple3-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.5 g, 1.3 mmol) with 3,3-dimethyl-1-butyne (0.311 mL, 2.5 mmol).Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1)to give3-tert-butoxycarbonyl-6-(3,3-dimethyl-but-1-ynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (304 mg, 74%).

Use a method similar to the General Procedure 1-5 to deprotect3-tert-butoxycarbonyl-6-(3,3-dimethyl-but-1-ynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by chromatography on silica gel eluting with DCM/2M ammonia inmethanol (1:0, 50:1, 20:1, 15:1 and 10:1) to obtain the free base of thetitle compound. Use a method similar to the General Procedure 2-1 togive the title compound as a tan solid (171 mg, 53%). MS (ES+) m/z: 228(M+H)⁺.

EXAMPLE 66-(3,3-Dimethyl-but-1-ynyl)-7-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 3 to couple7-fluoro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1 g, 2.4 mmol) with 3,3-dimethyl-1-butyne (0.599 mL, 4.9 mmol). Purifyby chromatography on silica gel eluting with hexane/EtOAc (10:1) to give6-(3,3-dimethyl-but-1-ynyl)-7-fluoro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (700 mg, 84%).

Use a method similar to the General Procedure 1-3 to deprotect6-(3,3-dimethyl-but-1-ynyl)-7-fluoro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by SCX chromatography followed by chromatography on silica geleluting with DCM/2M ammonia in methanol (1:0, 50:1, 20:1, 15:1 and 10:1)to obtain the free base of the title compound. Use a method similar tothe General Procedure 2-1 to give the title compound as a white solid(589 mg, 830%). MS (ES+) m/z: 246 (M+H)⁺.

General Procedure 4-1

Add7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1 equiv.), the appropriate alkylating agent (1.2 equiv.), ground K₂CO₃(3 equiv.) and KI (0.1 equiv.) to a proper solvent (acetone, ethanol oracetonitrile) and heat to reflux for 6 to 16 h unless otherwisespecified. Cool the reaction mixture to ambient temperature, quench with1N aqueous HCl and extract the aqueous layer three times with EtOAc.Combine the organic fractions, wash with saturated aqueous NaHCO₃,brine, dry over Na₂SO₄, filter and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc mixtures.

General Procedure 4-2

Add7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1 equiv.), the appropriate alcohol (1.1 equiv.), triphenylphosphine(1.2 equiv.) and diethyl azodicarboxylate (1.1 equiv.) sequentially toanhydrous THF. Stir the mixture at ambient temperature under nitrogen.Re-add triphenylphosphine (1.2 equiv.) and diethyl azodicarboxylate (1.1equiv.) if the reaction is not completed (monitored by TLC). Dilute themixture with EtOAc, wash with saturated aqueous NaHCO₃, brine, dry overNa₂SO₄ and concentrate in vacuo. Purify by chromatography on silica geleluting with hexane/EtOAc mixtures.

General Procedure 4-3

Add7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1 equiv.), the appropriate alcohol (1.2-1.5 equiv.) andtriphenylphosphine (1.5 equiv.) sequentially to anhydrous THF. Stir themixture at 0° C. under nitrogen for 10 min. Add1,1′-(azodicarbonyl)dipiperidine (1.5 equiv.) and let the mixture warmto ambient temperature over 16 h. Dilute with ether, filter andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc mixtures.

Preparation 67-Chloro-9-fluoro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine

1-Fluoro-4-methoxy-2-(2-nitro-vinyl)-benzene: Heat2-fluoro-5-methoxybenzaldehyde (15 g, 97.4 mmol) with nitromethane (32mL, 584 mmol) and ammonium acetate (30 g, 390 mmol) in acetic acid (136mL) under reflux for 30 min. Evaporate the solvent and dissolve theresidue in ether. Wash the organic fraction with water, saturatedaqueous NaHCO₃ and evaporate to give the desired intermediate (18.7 g,97%). GC-MS m/z: 197 (M)⁺.2-(2-Fluoro-5-methoxyphenyl)-ethylamine: Cautiously add sulfuric acid(14.7 mL, 265 mmol) dropwise at 0° C. to lithium aluminum hydride (1Msolution in THF, 565 mL) with efficient stirring. Warm the mixture toambient temperature for 20 min and then cool back to 0° C. Add asolution of 1-fluoro-4-methoxy-2-(2-nitro-vinyl)-benzene (18.7 g, 95mmol) in THF (150 mL) by cannula and stir 2.5 h at ambient temperature.Cool the mixture to 0° C., cautiously add water (4.6 mL) followed by 2Naqueous NaOH (4.6 mL) and water (6.5 mL). Remove the precipitate byfiltration and evaporate the filtrate to give the desired intermediate(16 g, 100%). MS (ES+) m/z: 170 (+H)⁺.N-(2,2-Dimethoxy-ethyl)-2,2,2-trifluoro-N-[2-(2-fluoro-5-methoxy-phenyl)-ethyl]-acetamide:Dissolve 2-(2-fluoro-5-methoxyphenyl)-ethylamine (16 g, 95 mmol) anddimethoxy acetaldehyde (60% aqueous, 21.5 mL, 142 mmol) in methanol (500mL). After 1.5 h, cautiously add sodium borohydride (5.39 g, 142 mmol)at 0° C. and then stir at ambient temperature for 3 h. Add acetone andevaporate the mixture. Dissolve the residue in DCM (250 mL), cool to 0°C. and add triethylamine (26.5 mL, 190 mmol) and trifluoroaceticanhydride (20.1 mL, 142 mmol). After 30 min, wash the mixture with 1Naqueous HCl (4×100 mL), brine and saturated aqueous NaHCO₃. Dry theorganic layer over Na₂SO₄ and concentrate in vacuo. Purify bychromatography on silica gel to give the desired intermediate (19.7 g,59%). MS (ES+) m/z: 322 (M-OMe)⁺.9-Fluoro-6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-benzo[d]azepine:DissolveN-(2,2-dimethoxy-ethyl)-2,2,2-trifluoro-N-[2-(2-fluoro-5-methoxy-phenyl)-ethyl]-acetamide(5 g, 14.2 mmol) in chlorobenzene (100 mL). Add polyphosphoric acid (5g) and P₂O₅ (2.5 g) and heat at 80° C. for 2 h. Add water to the hotmixture, cool to room temperature and extract with DCM. Dry the organicextracts over Na₂SO₄ and concentrate in vacuo to obtain the desiredintermediate (3.0 g, 73%). MS (ES+) m/z: 290 (M+H)⁺.9-Fluoro-6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve9-fluoro-6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-benzo[d]azepine(9.4 g, 32.4 mmol) with 10% Pd/C (dry basis, Degussa type, 1.4 g, 0.65mmol) in EtOAc/ethanol (1:1, 200 mL) and stir at ambient temperatureunder a balloon of hydrogen for 4.5 h. Filter the mixture through a padof silica gel and evaporate the filtrate to obtain the desiredintermediate (8.6 g, 91%). MS (ES+) m/z: 292 (M+H)⁺.9-Fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve9-fluoro-6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(8.1 g, 27.7 mmol) in DCM (250 mL), cool to 0° C. and add borontribromide (5.24 mL, 55.5 mmol). Stir at ambient temperature for 1.5 h,wash the mixture with brine, dry the organic layer over Na₂SO₄ andconcentrate in vacuo to obtain the desired intermediate (7.6 g, 99%). MS(ES+) m/z: 278 (M+H)⁺.7-Chloro-9-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve9-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.0 g, 3.6 mmol) in toluene (36 mL) with diisopropylamine (41 μL, 0.29mmol). Warm to 60° C. and add dropwise a solution of sulfuryl chloride(0.32 mL, 3.97 mmol) in toluene (10 mL). After 2 h, wash the mixturewith brine, dry the organic layer over Na₂SO₄ and evaporate onto silicagel. Purify by chromatography on silica gel eluting with EtOAc/hexane(0:1 to 1:0) to obtain the desired intermediate (1.0 g, 92%). MS (ES+)m/z: 312 (M+H)⁺.7-Chloro-9-fluoro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Cool a solution of7-chloro-9-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(2.5 g, 8.0 mmol), pyridine (3.25 mL, 40.2 mmol) and DCM (80 mL) at 0°C. and add dropwise trifluoromethanesulfonic anhydride (2.43 mL, 14.5mmol) over 20 min. Stir at room temperature for 1 h. Wash the reactionmixture sequentially with 1N aqueous HCl, saturated NaHCO₃ solution andbrine. Dry the organic fraction over Na₂SO₄ and concentrate in vacuo.Purify by chromatography on silica gel eluting with hexane/EtOAc(gradient from 19:1 to 1:1) to obtain the title compound (3.1 g, 87%).

Preparation 7 4-Bromomethyl-N-methyl-benzenesulfonamide

Mix 4-(bromomethyl)benzenesulfonyl chloride (2.7 g, 10 mmol), anhydrouspotassium carbonate (1.4 g, 10 mmol) and anhydrous THF (60 mL) undernitrogen. Cool the mixture in an ice bath, add dropwise a 2M solution ofmethylamine in THF, and stir at this temperature for 30 min. Remove theice bath and stir at ambient temperature for 16 h. Dilute with EtOActhen wash with 1N aqueous HCl. Separate the organic layer, dry overNa₂SO₄ and concentrate in vacuo. Purify by chromatography on silica geleluting with hexane/EtOAc (1:0, 4:1, 7:3 and 13:7) to obtain the titlecompound (1.5 g, 71%). MS (ES+) m/z: 266 (M+H)⁺.

The compounds of Preparations 8-9 may be prepared essentially asdescribed in Preparation 7 by using 4-(bromomethyl)benzenesulfonylchloride and the appropriate amine. Yields and MS (ES+) data are shownin the Table below.

Yield MS (ES+) Prep. NH—R Compound (%) m/z 8 NH—CH₂CH₃4-Bromomethyl-N-ethyl- 43 278 (M + H)⁺ benzenesulfonamide 9 NH—4-Bromomethyl-N-(2- 39 296 (M + H)⁺ CH₂CH₂F fluoroethyl)-benzenesulfonamide.

Preparation 10 Thiazol-2-yl-methanol

Mix under nitrogen 2-thiazolecarboxaldehyde (1.1 g, 10 mmol) and ethanol(30 mL). Add sodium borohydride (416 mg, 11 mmol) at 0° C. Stir and warmthe mixture slowly to ambient temperature for 12 h. Quench withsaturated aqueous ammonium chloride and concentrate in vacuo. Dilute theresidue with EtOAc and wash with brine. Dry the organic fraction overNa₂SO₄ and concentrate in vacuo to obtain the title compound as an oil(1.0 g, 87%). MS (ES+) m/z: 116 (M+H)⁺.

Preparation 11 (1-Methyl-1H-pyrazol-3-yl)-methanol

Dissolve 3-dimethoxymethyl-1-methylpyrazole (1.562 g, 10 mmol) inacetone (100 mL), add p-toluenesulfonic acid (190 mg, 1.0 mmol) and stirat ambient temperature for 12 h. Remove volatiles in vacuo, dissolve theresidue in EtOAc, wash with saturated aqueous NaHCO₃, dry over Na₂SO₄,filter and concentrate in vacuo to afford an oil. Dissolve the oil inmethanol (15 mL), add sodium borohydride (567 mg, 15 mmol) and stir thereaction mixture at ambient temperature for 12 h. Remove volatiles invacuo, dissolve the residue in EtOAc, wash with saturated aqueousNaHCO₃, dry over Na₂SO₄, filter and concentrate in vacuo. Purify bychromatography on silica gel eluting with EtOAc/hexane (6:1) to give thetitle compound as an oil (530 mg, 47%).

Preparation 126-(2-Amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

6-(2-tert-Butoxycarbonylamino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Use a method similar to the General Procedure 4-3, using7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(277 mg, 0.94 mmol) and N-(tert-butoxycarbonyl)ethanolamine (244 mg,1.51 mmol) to give, after chromatography on silica gel eluting withhexane/EtOAc (1:0 and 3:1), the desired intermediate (392 mg, 95%). MS(ES+) m/z: 337 (M+H-Boc)⁺.6-(2-Amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve6-(2-tert-butoxycarbonylamino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(997 mg, 2.28 mmol) in 4M hydrogen chloride in dioxane (15 mL) and stirat ambient temperature for 30 min. Concentrate to obtain thehydrochloride salt. Dissolve the salt in DCM and wash with saturatedaqueous NaHCO₃. Extract the basic aqueous layer with DCM. Dry thecombined organic extracts over MgSO₄, and concentrate in vacuo to affordthe title compound (731 mg, 95%). MS (ES+) m/z: 337 (M+H)⁺.

The compounds of Preparations 13-14 may be prepared essentially asdescribed in Preparation 12 by using7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate alcohol. Overall yields and MS (ES+) data are shownin the Table below.

Yield MS (ES+) Prep. n Compound (%) m/z 13 16-(3-Amino-propoxy)-7-chloro- 94 351 (M + H)⁺3-(2,2,2-trifluoroacetyl)-2,3,4,5- tetrahydro-1H-benzo[d]azepine 14 26-(4-Amino-butoxy)-7-chloro-3- 89 365 (M + H)⁺(2,2,2-trifluoroacetyl)-2,3,4,5- tetrahydro-1H-benzo[d]azepine

EXAMPLE 77-Chloro-6-(4-fluorobenzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Prepare a slurry of sodium hydride (60% in mineral oil; 99 mg, 2.5 mmol)in DMF (4 mL) and heat to 65° C. Add a solution of3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(250 mg, 0.84 mmol) in DMF (5 mL) dropwise and stir for 1 h. Add asolution of 4-fluorobenzyl bromide (191 mg, 1.0 mmol) in DMF (1 mL),stir at 65° C. for 1.5 h and cool to ambient temperature. Add water (1mL) and concentrate the mixture to an oily residue. Partition theresidue between EtOAc/hexane (1:1) and water. Dry the organic layer overNa₂SO₄, filter and concentrate in vacuo. Dissolve the residue in DCM,wash with 2N aqueous NaOH, dry the organic layer over Na₂SO₄, filter,and concentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (20:1, 10:1 and 7:1) to give3-tert-butoxycarbonyl-7-chloro-6-(4-fluorobenzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil.

Use a method similar to General Procedure 1-5 to deprotect3-tert-butoxycarbonyl-7-chloro-6-(4-fluorobenzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by SCX chromatography followed by chromatography on silica geleluting with DCM/2M ammonia in methanol (1:0, 50:1, 20:1, 15:1 and 10:1)to give the free base of the title compound. Use a method similar to theGeneral Procedure 2-1 to give the title compound as a white solid (178mg, 50%). MS (ES+) m/z: 306 (M+H)⁺.

EXAMPLE 87-Chloro-6-(4-cyanobenzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Combine3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.67 mmol), potassium carbonate (111 mg, 0.8 mmol), and4-cyanobenzyl bromide (263 mg, 1.34 mmol) in DMSO (5 mL) and heat thestirred mixture to 100° C. for 24 h. Cool to ambient temperature andpartition the mixture between water and EtOAc/hexane (1:1). Wash theorganic layer with brine and dry over Na₂SO₄, filter and concentrate invacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc(5:1) to give3-tert-butoxycarbonyl-7-chloro-6-(4-cyanobenzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil.

Use a method similar to the General Procedure 1-5 to deprotect3-tert-butoxycarbonyl-7-chloro-6-(4-cyanobenzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by SCX chromatography to give the free base of the titlecompound. Use a method similar to the General Procedure 2-2 to give thetitle compound as an off-white solid (66 mg, 27%). MS (ES+) z/z: 313(M+H)⁺.

EXAMPLE 97-Chloro-6-[2-(4-fluorophenyl)-2-oxo-oxy)]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 4-1, using7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(294 mg, 1.0 mmol) and 2-bromo-4′-fluoroacetophenone (260 mg, 1.2 mmol)to give, after purification by chromatography on silica gel eluting withhexane/EtOAc (7:1),7-chloro-6-[2-(4-fluorophenyl)-2-oxo-ethoxy)]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a solid (402 mg, 93%). MS (ES+) m/z: 430 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-[2-(4fluorophenyl)-2-oxo-ethoxy)]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(402 mg, 0.93 mmol). Purify by chromatography on silica gel eluting withDCM/2M ammonia in methanol (96:4) to give the free base of the titlecompound (278 mg, 89%). MS (ES+) m/z: 334 (M+H)⁺. Use a method similarto the General Procedure 2-3 to give the title compound.

EXAMPLE 107-Chloro-6-(4-methylsulfamoyl-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Dissolve under nitrogen7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.68 mmol) in acetone (30 mL). Add powdered anhydrous potassiumcarbonate (276 mg, 2.0 mmol) and powdered potassium iodide (11.3 mg,0.068 mmol) followed by 4-bromomethyl-N-methyl-benzenesulfonamide (528mg, 2.0 mmol). Stir the reaction mixture at ambient temperature for 12h. Concentrate in vacuo, dilute with EtOAc and wash twice with 1Naqueous HCl. Separate the organic layer, dry over Na₂SO₄ and concentratein vacuo. Purify by chromatography on silica gel eluting withhexane/EtOAc (1:0 and 4:1) to obtain7-chloro-6-(4-methylsulfamoyl-benzyloxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(201 mg, 60%).

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-(4-methylsulfamoyl-benzyloxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(196 mg, 0.41 mmol). Purify by SCX column to give the free base of thetitle compound (110 mg, 70%). MS (ES+) m/z: 381 (M+H)⁺. Use a methodsimilar to the General Procedure 2-2 to obtain the title compound.

Examples 11-12 may be prepared essentially as described in Example 10 byusing7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate bromide. MS (ES+) data are shown in the Table below.

MS (ES+) Ex. NH—R Compound m/z 11 NH—CH₂—CH₃7-Chloro-6-(4-ethylsulfamoyl- 395 benzyloxy)-2,3,4,5-tetrahydro-1H- (M +H)⁺ benzo[d]azepine Hydrochloride 12 NH—CH₂—CH₂F 7-Chloro-6-[4-(2- 413fluoroethylsulfamoyl)- (M + H)⁺ benzyloxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepine Hydrochloride

EXAMPLE 13 Allen 17-Chloro-9-fluoro-6-(4-fluorobenzyloxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Dissolve7-chloro-9-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.25 g, 0.8 mmol) in DMF (8 mL), add potassium carbonate (0.56 g, 4.0mmol) and 4-fluorobenzyl bromide (0.46 mL, 2.4 mmol). After 14 h at 90°C., dilute with ether and wash with brine. Dry the organic layer overNa₂SO₄ and evaporate onto silica gel. Purify by chromatography on silicagel eluting with EtOAc/hexane (0:1 to 1:0) to obtain7-chloro-9-fluoro-6-(4-fluorobenzyloxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.

Use a method similar to the General Procedure 1-1, using7-chloro-9-fluoro-6-(4-fluorobenzyloxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine,to give the free base of the title compound. Use a method similar to theGeneral Procedure 2-2 to obtain the title compound (275 mg, 95%). HRMScalc'd for C₁₇H₁₇NOF₂Cl 324.0902, found 324.0957.

EXAMPLE 147-Chloro-6-(pyridin-2-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Prepare a slurry of sodium hydride (60% in mineral oil, 168 mg, 4.2mmol) in DMF (4 mL) and heat to 65° C. Add dropwise a solution of3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(250 mg, 0.84 mmol) in DMF (5 mL) and stir for 1 h. Add a solution of2-(bromomethyl)-pyridine hydrobromide (256 mg, 1 mmol) in DMF (1 mL),stir at 65° C. for 0.5 h and cool to ambient temperature. Add water (1mL) and concentrate the reaction mixture to an oily residue. Partitionthe residue between EtOAc/hexane (1:1) and water. Dry the organic layerover Na₂SO₄, filter and concentrate. Purify by chromatography on silicagel eluting with hexane/EtOAc (10:1, 5:1 and 3:1) to give3-tert-butoxycarbonyl-7-chloro-6-(pyridin-2-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil.

Use a method similar to the General Procedure 1-5 to deprotect3-tert-butoxycarbonyl-7-chloro-6-(pyridin-2-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by SCX chromatography to give the free base of the titlecompound. Use a method similar to the General Procedure 2-1 to give thetitle compound as a white solid (228 mg, 67%). MS (ES+) m/z: 289 (M+H)⁺.

EXAMPLE 157-Chloro-6-(pyridin-3-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineDisuccinate

Use a method similar to the Example 14, using3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(250 mg, 0.84 mmol) and 3-(bromomethyl)-pyridine hydrobromide (256 mg, 1mmol) to give the free base of the title compound. Use a method similarto the General Procedure 2-1 with two equivalents of succinic acid togive the title compound as a white solid (354 mg, 80%). MS (ES+) m/z:289 (M+H)⁺.

EXAMPLE 167-Chloro-6-(thiazol-2-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 4-2, using7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand thiazol-2-yl-methanol (86.2 mg, 0.75 mmol) to give, afterchromatography on silica gel eluting with hexane/EtOAc (9:1 and 7:3),7-chloro-6-(thiazol-2-ylmethoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(163 mg, 61%). MS (ES+) m/z 391 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-(thiazol-2-ylmethoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by chromatography on silica gel eluting with DCM/2M ammonia inmethanol (94:6) to obtain the free base of the title compound (99 mg,81%). MS (ES+) m/z: 295 (M+H)⁺. Use a method similar to the GeneralProcedure 2-2 to give the title compound.

EXAMPLE 177-Chloro-6-(thiazol-5-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 4-2, using7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(294 mg, 1.0 mmol) and 5-hydroxymethylthiazole (127 mg, 1.1 mmol) togive, after chromatography on silica gel eluting with EtOAc/hexane(1:3),7-chloro-6-(thiazol-5-ylmethoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (350 mg, 89%). MS (ES+) m/z: 391 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-(thiazol-5-ylmethoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(350 mg, 0.90 mmol). Purify by chromatography on silica gel eluting withDCM/2M ammonia in methanol (95:5) to give the free base of the titlecompound (203 mg, 76%). MS (ES+) m/z: 295 (M+H)⁺. Use a method similarto the General Procedure 2-2 to give the title compound.

Examples 18-19 may be prepared essentially as described in Example 17 byusing7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate alcohol. Overall yields and MS (ES+) data are shownin the Table below.

Yield MS (ES+) Ex. O—R Compound (%) m/z 18

7-Chloro-6-(5-methyl-isoxazol-3-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride47 293(M + H)⁺ 19

7-Chloro-6-(1-methyl-1H-pyrazol-3-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride39 292(M + H)⁺

EXAMPLE 207-Chloro-6-(3-methylthio-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 4-2, using7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 3-(methylthio)-1-propanol (191 mg, 1.8 mmol) to give, afterchromatography on silica gel eluting with EtOAc/hexane (1:8),7-chloro-6-(3-methylthio-propoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (65 mg, 14%).

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-(3-methylthio-propoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(65 mg, 0.17 mmol). Purify by chromatography on silica gel eluting withDCM/2M ammonia in methanol (94:6) to give the free base of the titlecompound (25 mg, 51%). MS (ES+) m/z: 286 (M+1)⁺. Use a method similar tothe General Procedure 2-1 to give the title compound.

EXAMPLE 217-Chloro-6-(4-methylthio-butoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the Example 20, using7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4-(methylthio)-1-butanol to give the title compound. MS (ES+) m/z:300 (M+1)⁺.

EXAMPLE 227-Chloro-6-(3-pyridin-2-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 4-3, using7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(50 mg, 0.17 mmol) and 3-(2-pyridyl)-1-propanol (35 mg, 0.255 mmol) togive, after reverse phase HPLC (10-95% of solvent B in 12.8 min, 25mL/min; solvent A: water, 0.1% trifluoroacetic acid; solvent B:acetonitrile, 0.1% trifluoroacetic acid; column: YMC SH-341-5, S-5□m, 12nm, 100×20 mm),7-chloro-6-(3-pyridin-2-yl-propoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.

Use a method similar to the General Procedure 1-1, using7-chloro-6-(3-pyridin-2-yl-propoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give the free base of the title compound. Use a method similar to theGeneral Procedure 2-2 to give the title compound as a solid (26 mg,39%). MS (ES+) m/z: 317 (M+H)⁺.

Examples 23-26 may be prepared essentially as described in Example 22 byusing7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate alcohol. Overall yields and MS (ES+) data are shownin the Table below.

Yield MS (ES+) Ex. O—R Compound (%) m/z 23

7-Chloro-6-[2-(4-methyl-thiazol-5-yl)-ethoxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride83 323(M + H)⁺ 24

7-Chloro-6-(2-pyridin-2-yl-ethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 83 303(M + H)⁺ 25

7-Chloro-6-(3-pyridin-3-yl-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 83 317(M + H)⁺ 26

6-[3-(1H-Benzimidazol-2-yl)-propoxy]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride8 356(M + H)⁺

EXAMPLE 27

6-(2-Benzoylamino-ethoxy)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Combine benzoyl chloride (19.3 mg, 0.137 mmol), PS-morpholine (109 mg,0.272 mmol),6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(46 mg, 0.137 mmol) in DCM (1.5 mL) and stir at ambient temperature for16 h. Filter the resin, wash with DCM and concentrate in vacuo. Purifyby reverse phase HPLC (10-95% of solvent B in 12.8 min, 25 mL/min;solvent A: water, 0.1% trifluoroacetic acid; solvent B: acetonitrile,0.1% trifluoroacetic acid; column: YMC SH-341-5, S-5 μm, 12 nm, 100×20mm) to give6-(2-benzoylamino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.

Use a method similar to the General Procedure 1-1, using6-(2-benzoylamino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give the free base of the title compound. Use a method similar to theGeneral Procedure 2-2 to give the title compound as a solid (51 mg,98%). MS (ES+) m/z: 345 (M+H)⁺.

Examples 28-40 may be prepared essentially as described in Example 27,using6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineor6-(3-amino-propoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineor6-(4-amino-butoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate acyl chloride. Overall yields and MS (ES+) data areshown in the Table below.

Yield MS (ES+) Ex. NH—CO—R n Compound (%) m/z 28

27-Chloro-6-[2-(4-chlorobenzoylamino)-ethoxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 46 380(M + H)⁺ 29

27-Chloro-6-[2-(3-chlorobenzoylamino)-ethoxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 63 380(M + H)⁺ 30

27-Chloro-6-[2-(2-chlorobenzoylamino)-ethoxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 18 380(M + H)⁺ 31

27-Chloro-6-[2-(4-fluorobenzoylamino)-ethoxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 18 363(M + H)⁺ 32

27-Chloro-6-{2-[(pyridine-4-carbonyl)-amino]-ethoxy}-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride  4 346(M + H)⁺ 33

27-Chloro-6-[2-(cyclopropanecarbonyl-amino)-ethoxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 47 309(M + H)⁺ 34

27-Chloro-6-{2-[(pyrrolidine-1-carbonyl)-amino]-ethoxy}-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride  6 338(M + H)⁺ 35

27-Chloro-6-[2-(cyclohexanecarbonyl-amino)-ethoxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 40 351(M + H)⁺ 36

37-Chloro-6-(3-ethoxycarbonylamino-propoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 63 327(M + H)⁺ 37

36-(3-Benzoylamino-propoxy)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 72 359(M + H)⁺ 38

37-Chloro-6-{3-[(pyridine-4-carbonyl)-amino]-propoxy}-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 12 360(M + H)⁺ 39

47-Chloro-6-(4-ethoxycarbonylamino-butoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 49 341(M + H)⁺ 40

46-(4-Benzoylamino-butoxy)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 56 373(M + H)⁺

EXAMPLE 417-Chloro-6-[2-(2-fluorobenzoylamino)-ethoxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Dissolve6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(100 mg, 0.297 mmol) in DCM (5 mL). Add 2-fluorobenzoyl chloride (39 μL,0.326 mmol), triethylamine (62 μL, 0.445 mmol) and stir at ambienttemperature for 72 h under nitrogen atmosphere. Dilute with DCM, add 1Maqueous HCl and extract the aqueous phase with DCM. Dry the combinedorganic extracts over MgSO₄ and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (7:3 and 2:1) togive7-chloro-6-[2-(2-fluorobenzoylamino)-ethoxy]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(111 mg, 820%).

Use a method similar to the General Procedure 1-1, using7-chloro-6-[2-(2-fluorobenzoylamino)-ethoxy]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give the free base of the title compound. Use a method similar to theGeneral Procedure 2-2 to give the title compound as a solid (12 mg,95%). MS (ES+) m/z: 363 (M+H)⁺.

EXAMPLE 427-Chloro-6-{2-[(pyridine-2-carbonyl)-amino]-ethoxy}-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Combine picolinic acid (40 mg, 0.327 mmol), EDC (57 mg, 0.297 mmol) andHOBT (40 mg, 0.297 mmol) in DCM (3 mL). Stir for 10 min at ambienttemperature. Add6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(100 mg, 0.297 mmol). Stir for 16 h at ambient temperature. Dilute withDCM, add water and extract the aqueous layer with DCM. Wash the combinedorganic extracts with 1M aqueous NaOH and brine. Dry the organic layerover MgSO₄ and concentrate in vacuo. Purify by chromatography on silicagel eluting with hexane/EtOAc (3:2) to give7-chloro-6-{2-[(pyridine-2-carbonyl)-amino]-ethoxy}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(94 mg, 74%).

Use a method similar to the General Procedure 1-1, using7-chloro-6-{2-[(pyridine-2-carbonyl)-amino]-ethoxy}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give the free base of the title compound. Use a method similar to theGeneral Procedure 2-2 to give the title compound as a solid (81 mg,72%). MS (ES+) m/z: 346 (M+H)⁺.

EXAMPLE 437-Chloro-6-{2-[(pyridine-3-carbonyl)-amino]-ethoxy}-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to Example 42, using nicotinic acid (40 mg, 0.327mmol) and6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(100 mg, 0.297 mmol) to give the title compound as a solid (105 mg,93%). MS (ES+) m/z: 346 (M+H)⁺.

EXAMPLE 447-Chloro-6-[2-(3-phenyl-ureido)-ethoxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Combine phenyl isocyanate (16.3 mg, 0.137 mmol),6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(46 mg, 0.137 mmol) in DCM (1.5 mL) and stir at ambient temperature for16 h. Concentrate in vacuo. Purify by reverse phase HPLC (10-95% ofsolvent B in 12.8 min, 25 mL/min; solvent A: water, 0.1% trifluoroaceticacid; solvent B: acetonitrile, 0.1% trifluoroacetic acid; column: YMCSH-341-5, S-5 μm, 12 nm, 100×20 mm) to give7-chloro-6-[2-(3-phenyl-ureido)-ethoxy]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.

Use a method similar to the General Procedure 1-1, using7-chloro-6-[2-(3-phenyl-ureido)-ethoxy]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give the free base of the title compound. Use a method similar to theGeneral Procedure 2-2 to give the title compound as a solid (8 mg, 15%).MS (ES+) m/z: 360 (M+H)⁺.

Examples 45-46 may be prepared essentially as described in Example 44 byusing phenyl isocyanate and the appropriate6-(3-amino-propoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineor6-(4-amino-butoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Overall yields and MS (ES+) data are shown in the Table below.

Yield MS (ES+) Ex. NH—CO—R n Compound (%) m/z 45

37-Chloro-6-[3-(3-phenyl-ureido)-propoxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 36 374(M + H)⁺ 46

47-Chloro-6-[4-(3-phenyl-ureido)-butoxy]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 28 388(M + H)⁺

EXAMPLE 487-Chloro-6-(3-methoxycarbonyl-propyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Add methyl 4-bromobutyrate (1.9 mL, 10.4 mmol) to a mixture of3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-benzo[d]azepine(310 mg, 1.0 mmol), DBU (0.23 mL, 1.6 mmol) and DMF (10 mL) at ambienttemperature under nitrogen. Stir the reaction mixture for 16 h. Dilutewith hexane/EtOAc (1:1, 60 mL), wash the mixture with 10% aqueous NaCl(4×25 mL), dry the organic layer over Na₂SO₄ and concentrate in vacuo.Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1to 2:3) to obtain3-tert-butoxycarbonyl-7-chloro-6-(3-methoxycarbonyl-propyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(303 mg, 73%). MS (ES+) m/z: 398 (+H)⁺.

Use a method similar to the General Procedure 1-5 to deprotect3-tert-butoxycarbonyl-7-chloro-6-(3-methoxycarbonyl-propyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(295 mg, 0.74 mmol). Purify by SCX chromatography followed bychromatography on silica gel eluting with DCM/2M ammonia in methanol(99:1 to 90:10) to give the free base of the title compound. Use amethod similar to the General Procedure 2-1 to give the title compound(160 mg, 52%). MS (ES+) m/z: 298 (M+H)⁺.

General Procedure 5-1

Dissolve the appropriately substituted3-(2,2,2-trifluoroacetyl)-6-trifluoromethane-sulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine-(1equiv.), palladium(II) acetate (0.1-0.4 equiv.), BINAP (0.2-0.8 equiv.;BINAP/catalyst ratio 2:1) and cesium carbonate (1.4-3.0 equiv.) intoluene (0.2-0.05 M solution). Add the amine (1-3 equiv.), degas themixture with vacuum/nitrogen or argon purge and heat at 80-110° C. for4-16 h. Cool the mixture to ambient temperature, dilute with EtOAc,filter through a pad of silica gel or through Celite® washing with EtOAcor ether, and evaporate the solvent to obtain the crude mixture.Alternatively, partition the reaction mixture between brine or saturatedaqueous NaHCO₃ and EtOAc, ether or DCM, dry the organic layer overNa₂SO₄, and concentrate to obtain the crude mixture. Purify the crudemixture by chromatography on silica gel eluting with hexane/EtOAcmixtures and further SCX chromatography if needed.

General Procedure 5-2

Dissolve the appropriately substituted3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1 equiv.), tris(dibenzylideneacetone)dipalladium(0) (0.1-0.5 equiv.),BINAP (0.2-1.0 equiv.; BINAP/catalyst ratio 2:1) and cesium carbonate(1.4 equiv.) in toluene (0.05-0.5 M solution). Degas under vacuum andfill three times with nitrogen. Add the appropriately substituted amine(1.0-5.0 equiv.) and heat the mixture to 80-100° C. for 2-16 h in asealed flask under a nitrogen atmosphere. Cool the reaction flask toambient temperature, dilute the mixture with EtOAc or DCM, filterthrough Celite® and concentrate in vacuo. Purify by chromatography onsilica gel eluting with hexane/EtOAc mixtures and further SCXchromatography if needed.

General Procedure 5-3

Add the appropriately substituted3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1 equiv.), the appropriate amine (1.2-3.0 equiv.), palladium(II)acetate (0.2-0.4 equiv.), tris(dibenzylideneacetone)dipalladium(0)(0.1-0.2 equiv.), BINAP (0.6-1.2 equiv.; BINAP/catalysts ratio 2:1),cesium carbonate (2-2.5 equiv.) and toluene or 1,4-dioxane (0.05-0.2 Msolution) to a flask, degas and fill three times with nitrogen. Heat themixture at 80-100° C. for 10-16 h. Dilute the mixture with EtOAc, washwith saturated aqueous NaHCO₃ and brine, dry over Na₂SO₄, filter andconcentrate in vacuo to give the crude mixture. Alternatively remove thevolatiles from the reaction mixture to give directly the crude mixture,or filter the reaction mixture through Celite® and concentrate in vacuo.Purify by chromatography on silica gel eluting with hexane/EtOAcmixtures and further SCX chromatography if needed.

General Procedure 54

Combine6-amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine,the appropriate bromide (1.0-2.0 equiv.), potassium or cesium carbonate(1.0-2.0 equiv.) and toluene, DMF or acetonitrile in a sealed tube andheat at 50-150° C. for 3-72 h. Cool to ambient temperature and evaporatethe solvent in vacuo to obtain the crude mixture. Alternatively,partition the reaction mixture between diethyl ether/brine (1:1), drythe organic layer over anhydrous Na₂SO₄ and concentrate to obtain thecrude mixture. Purify by chromatography on silica gel eluting withhexane/EtOAc (1:0, 9:1, 4:1, 7:3 and 3:2).

General Procedure 6-1

Dissolve 4-(tert-butoxycarbonylamino-methyl)-benzoic acid (1 equiv.),HATU (1 equiv.), DIEA (2 equiv.) and the appropriately substituted amine(1 equiv.) in DCM or DCM/DMF and stir at ambient temperature for 4-16 h.Concentrate in vacuo, dissolve the residue in DCM and wash successivelywith saturated aqueous NaHCO₃, 1N aqueous HCl, water, brine, and dryover Na₂SO₄. Filter and concentrate the solution and use the materialwithout further purification. Deprotect the residue using the GeneralProcedure 1-5 and purify by SCX chromatography.

General Procedure 6-2

Dissolve 4-(tert-butoxycarbonylamino-methyl)-benzoic acid or5-(tert-butoxycarbonylamino-methyl)-pyridine-2-carboxylic acid lithiumsalt (1 equiv.), HATU (1 equiv.), DIEA (2 equiv.) and the appropriatelysubstituted amine (1 equiv.) in DCM or DCM/DMF and stir at ambienttemperature for 4-16 h. Concentrate in vacuo, dissolve the residue inDCM and wash successively with saturated aqueous NaHCO₃, water, brine,and dry over Na₂SO₄. Filter and concentrate the solution and use thematerial without further purification. Deprotect the residue using theGeneral Procedure 1-5 and purify by SCX chromatography.

General Procedure 6-3

Dissolve the appropriately substituted acetophenone (1.0-1.2 equiv.) inTHF, add titanium(IV) ethoxide (33-35% TiO₂, 2.0 equiv.) and thecorresponding (R)-2-methyl-2-propanesulfinamide or(S)-2-methyl-2-propanesulfinamide (1.0 equiv.). Heat the mixture to40-60° C. for 2-16 h under a nitrogen atmosphere. Cool the reaction to−78° C., then add the cold mixture over 3-10 min to a slurry ofTHF/NaBH₄ (2-4 M) at −78° C. Allow the mixture to warm up to ambienttemperature over 2-16 h. Pour the mixture into brine, filter theresulting slurry through Celite® and wash thoroughly with EtOAc.Concentrate in vacuo. Dilute the oil with EtOAc, wash with brine andextract the aqueous phase with EtOAc. Dry the combined organic extractsover Na₂SO₄ and concentrate in vacuo. Purify the crude sulfinamide onsilica gel eluting with hexane/EtOAc mixtures to obtain the majordiastereomer. Dissolve the major diastereomer in excess of 4M hydrogenchloride in dioxane, stir the mixture for 1 h and concentrate in vacuoto a solid. Slurry the solid in diethyl ether, then filter in vacuo toobtain the hydrochloride salt of the desired amine. The free base of theamine is prepared either via SCX chromatography or by basic extraction.

General Procedure 6-4

Add the appropriately substituted benzonitrile portion wise to a flaskcontaining a slurry of lithium aluminum hydride (3.0-6.0 equiv.) indiethyl ether (0.1-0.3 M solution) under a nitrogen atmosphere. Stir themixture for 1 h and quench slowly with water (0.5-2.0 mL), followed by5N aqueous NaOH (0.5-2.0 mL). Filter the slurry through Celite® and washthe cake with diethyl ether. Concentrate in vacuo to obtain the desiredamine. If additional purification is needed, dissolve the amine in etherand add an excess of 2M hydrogen chloride in ether. Filter to obtain thedesired amine as the hydrochloride salt. Prepare the free base by usingSCX chromatography or by dissolving the hydrochloride salt in an aqueoussolution of cesium carbonate (1.0-5.0 equiv.) or saturated aqueousNaHCO₃ (1.0-5.0 equiv.). Extract the mixture with DCM or toluene, dryover Na₂SO₄ and concentrate in vacuo to obtain the amine.

General Procedure 6-5

Add BH₃-T complex (1-3 equiv., 1M solution in THF) dropwise to asolution of appropriately substituted benzonitrile in anhydrous THF atroom temperature then stir overnight. Alternatively the reaction can beheated at reflux overnight Add either methanol or aqueous HCl (3 equiv.)cautiously at room temperature and stir vigorously until gaseousevolution stops. Concentrate in vacuo, basify and then extract intoEtOAc. Wash the organic phase with brine, dry over MgSO₄ and concentratein vacuo. Purify by SCX chromatography eluting with methanol followed bya solution of ammonia in methanol (3-7 M) to give the desiredbenzylamine.

Preparation 157-Cyano-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine

7-Bromo-6-hydroxy-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(18 g, 69.4 mmol) and DIEA (0.98 mL) in DCM (1.4 L). Add dropwise asolution of NBS (12.4 g, 69.4 mmol) in DCM (500 mL) over 75 min. Stirthe reaction mixture at ambient temperature for 1 h, pour into water(500 mL) and extract the mixture with DCM. Wash the organic fractionwith brine, dry over Na₂SO₄, filter and concentrate. Purify bychromatography on silica gel eluting with hexane/EtOAc (4:1) to give thedesired intermediate as a white solid (20.9 g, 89%). MS (ES−) m/z: 337(M−H)⁻.7-Cyano-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add copper nitrile (2.6 g, 28 mmol) to a solution of7-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(2.4 g, 7.0 mmol) in anhydrous NMP (45 mL), degas and purge withnitrogen and heat to 150° C. for 18 h. Allow the reaction mixture tocool to ambient temperature and then dilute with EtOAc/heptane (2:1) andfilter through a silica pad. Dilute the filtrate with water, and extractthe aqueous phase twice with EtOAc. Dry the combined organic extractsover MgSO₄, filter and concentrate in vacuo. Purify by chromatography onsilica gel eluting with EtOAc/heptane (1:4 to 1:1) to obtain the desiredintermediate as an orange oil (1.7 g, 86%). MS (ES−) m/z: 283 (M−H)⁻.7-Cyano-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add dry pyridine (3 mL) to7-cyano-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.1 g, 3.9 mmol) in anhydrous DCM (45 mL) and cool to 0° C. Add slowlytrifluoromethanesulfonic anhydride (1.3 mL, 7.7 mmol), allow thereaction mixture to warm to ambient temperature and stir for 3 h. Dilutewith DCM and wash with 2N aqueous HCl. Dry the organic layer over MgSO₄,filter and concentrate in vacuo to obtain the title compound as anorange/brown oil (1.6 g, 100%) that was used without purification. MS(ES−) m/z: 415 (M−H)⁻.

Preparation 163-(2,2,2-Trifluoroacetyl)-6-trifluoromethanesulfonyloxy-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

6-Hydroxy-7-iodo-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.037 g, 4.0 mmol) and diisopropylamine (60.7 mg, 0.6 mmol) toanhydrous DCM (350 mL) and stir at 10-20° C. Add slowly a solution ofN-iodosuccinimide (1.035 g, 4.6 mmol) in DCM (100 mL) over a period of 3h. Stir the reaction mixture overnight and gradually warm to ambienttemperature. Quench the reaction with saturated aqueous NaHCO₃, separatethe organic layer, wash the organic layer with 0.1N aqueous HCl, brine,dry over Na₂SO₄, filter and concentrate in vacuo. Purify bychromatography on silica gel eluting with EtOAc/hexane (1:20 to 1:10) togive the desired intermediate as a white solid (1.0 g, 65%). MS (ES+)m/z: 386 (M+H)⁺.7-Iodo-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add triethylamine (496 mg, 4.90 mmol) to a solution of6-hydroxy-7-iodo-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(945 mg, 2.45 mmol) in DCM (30 mL) at O—C. Add dropwisetrifluoromethanesulfonic anhydride (1.244 g, 4.41 mmol) and stir at 0°C. for 1 h. Warm to ambient temperature overnight. Dilute the mixturewith DCM, wash with water, saturated aqueous NaHCO₃ and brine. Dry overNa₂SO₄, filter and concentrate in vacuo. Purify by chromatography onsilica gel eluting with EtOAc/hexane (1:6) to give the desiredintermediate as a white solid (1.246 g, 98%). MS (ES+) m/z: 518 (M+H)⁺.3-(2,2,2-Trifluoroacetyl)-6-trifluoromethanesulfonyloxy-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add CuI (367 mg, 1.93 mmol), methyl2,2-difluoro-2-(fluorosulfonyl)acetate (1.852 g, 9.64 mmol) and HMPA(1.728 g, 9.64 mmol) to a solution of7-iodo-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.246 g, 2.41 mmol) in DMF (8 mL) and heat the mixture at 70° C. for1.5 h. Add same amount of CuI, methyl2,2-difluoro-2-(fluorosulfonyl)acetate, and HMPA and stir further for 4h. Cool the mixture to ambient temperature, quench with saturatedaqueous ammonium chloride, separate the organic layer, and extract theaqueous layer with EtOAc three times. Combine the organic layers, washwith saturated aqueous NaHCO₃, brine, dry over Na₂SO₄, filter andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith EtOAc/hexane (1:20 to 1:10) to give the title compound as a whitesolid (321 mg, 29%) and to recover the starting material (741 mg, 59%).MS (ES+) m/z: 460 (M+H)⁺.

Preparation 177-Ethyl-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine

9-Bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add dropwise bromine (10.8 mL, 0.21 mol) in acetonitrile (260 mL) to aslurry of6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(51.8 g, 0.2 mol) in acetonitrile (400 mL) at 0° C. cooling withice-water to keep the temperature between 2-5° C. Warm the reaction toambient temperature and stir for 30 min. Pour the mixture into ice-coldwater (2 L) to obtain a white precipitate. Collect the solid by vacuumfiltration, wash with water and dry under vacuum at 105° C.Recrystallize the crude material in toluene/heptane and cool the mixturein an ice bath. Collect the solid by vacuum filtration, wash withheptane and dry under vacuum at 105° C. to obtain the desiredintermediate as a white solid (54.63 g, 81%). MS (ES+) m/z: 338 (M+H)⁺.6-Acetoxy-9-bromo-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Under nitrogen atmosphere, mix9-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(6 g, 17.8 mmol), anhydrous pyridine (0.06 mL, 0.72 mmol), DMAP (222 mg,1.8 mmol) and acetic anhydride (30 mL). Heat the mixture at reflux for 8h and then stir at ambient temperature for another 8 h. Concentrate invacuo, dilute the residue in EtOAc, wash with 1N aqueous HCl, and thenwith saturated aqueous NaHCO₃. Dry the organic layer over Na₂SO₄,filter, and concentrate in vacuo to obtain the desired intermediate(5.64 g, 84%) that was used without further purification. MS (ES+) m/z:380 (M+H)⁺.7-Acetyl-9-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Under nitrogen atmosphere, mix6-acetoxy-9-bromo-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(2.8 g, 7.4 mmol) and nitrobenzene (5 mL). Add anhydrous aluminumchloride (980 mg, 7.4 mmol). Heat at 180° C. for 2 h. Cool the mixtureto ambient temperature. Add-concentrated HCl (10 mL) dropwise. Stir themixture for 30 min. Add 1N aqueous HCl then extract with EtOAc. Dry theorganic layer over Na₂SO₄, filter and concentrate in vacuo. Purify bychromatography on silica gel eluting with EtOAc/hexane (0:1 to 1:4) toafford the desired intermediate (833 mg, 30%). MS (ES−) m/z: 378 (M−H)⁻.7-Acetyl-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Mix-acetyl-9-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(833 mg, 2.2 mmol), tetrakis(triphenylphosphine)palladium(0) (150 mg,0.13 mmol) and sodium formate (224 mg, 3.3 mmol) in anhydrous DMF (15mL). Degas twice then flush with argon. Keep the flask under argon andheat the reaction at 95° C. for 16 h. Dilute with EtOAc then wash with1N aqueous HCl. Separate the organic layer, dry over Na₂SO₄, filter andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith EtOAc/hexane (0:1, 1:9 and 1:4) to give the desired intermediate(448 mg, 68%). MS (ES+) m/z: 302 (+H)⁺.7-Ethyl-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Under nitrogen dissolve7-acetyl-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.0 g, 3.32 mmol) in anhydrous THF (100 mL). Cool the solution to 0°C., add boron trifluoride diethyl etherate (3.4 mL, 26.6 mmol) andsodium cyanoborohydride (836 mg, 13.3 mmol). Remove the ice bath andstir for 5 h at ambient temperature. Dilute with EtOAc and wash with0.1N aqueous HCl. Separate the organic layer, dry over Na₂SO₄, filterand concentrate in vacuo. MS (ES−) m/z: 302 (M−H)⁻. Mix the residue withtrifluoroacetic acid (40 mL) and anhydrous DCM (50 mL) under nitrogen.Cool to 0° C. in an ice bath and add triethyl silane (3.5 mL, 21.9mmol). After 15 min, remove the ice bath and stir at ambient temperaturefor 16 h. Concentrate in vacuo and purify by chromatography on silicagel eluting with EtOAc/hexane (1:9) to obtain the desired intermediate(698 mg, 73%). MS (ES−) m/z: 286 (M−H)⁻.7-Ethyl-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Under nitrogen mix7-ethyl-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(698 mg, 2.4 mmol), triethylamine (0.67 mL, 4.8 mmol) and anhydrous DCM(25 mL). Cool the mixture in an ice bath, add dropwisetrifluoromethanesulfonic anhydride (0.81 mL, 4.8 mmol) and stir atambient temperature for 3 h. Quench with water and extract three timeswith DCM. Wash the organic extracts with 0.1N aqueous HCl and brine. Dryover Na₂SO₄, filter and concentrate to obtain the title compound (1.0 g,100%). MS (ES+) m/z: 420 (M+H)⁺.

Preparation 187-Propyl-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine

6-Allyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1 g, 3.9 mmol) in acetone (5 mL) and add powdered potassium carbonate(2.8 g, 20 mmol). Add dropwise a solution of alkyl bromide (1.04 mL, 12mmol) in acetone (3 mL) over 10 min and stir at ambient temperatureovernight. Filter solids, wash with acetone and concentrate in vacuo togive the desired intermediate as an off-white solid (1.15 g, 98%). GC-MSm/z: 299 (M⁺).7-Allyl-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve6-alkyloxy-3-(2,7-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.1 g, 3.7 mmol) in DCM (15 mL) and cool to −15° C. Add 1M borontrichloride in DCM (15 mL, 15 mmol) and warm to ambient temperature.Stir for 30 min at ambient temperature. Add water (50 mL) and extractthe aqueous layer three times with DCM. Wash the combined organicextracts with water (100 mL), brine (100 mL), dry over MgSO₄, filter,and concentrate in vacuo to give the desired intermediate (980 mg, 89%)as a light yellow oil which solidified to an off-white solid uponstanding at ambient temperature. MS (ES+) m/z: 300 (M+H)⁺.6-Hydroxy-7-propyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve7-alkyl-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.5 g, 5 mmol) in EtOAc (50 mL) containing 10% Pd/C (1.3 g). Stir atambient temperature at 1 atm with H₂ (balloon) for 30 min. Filter thecatalyst and wash with water (100 mL). Extract the resulting filtratethree times with EtOAc, wash the combined organic extracts with brine,dry over MgSO₄, filter and concentrate in vacuo to give the desiredintermediate as a white solid (1.45 g, 97%). MS (ES+) m/z: 302 (M+H)⁺.7-Propyl-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Cool a solution of6-hydroxy-7-propyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(500 mg, 1.9 mmol), triethylamine (390 μL, 2.3 mmol) and DCM (20 mL) ina cryogenic bath set at −35° C. and add dropwise over 20 mintrifluoromethanesulfonic anhydride (325 μL, 2.3 mmol). Stir at thistemperature overnight. Wash the reaction mixture sequentially withwater, 1N aqueous HCl, water, and brine. Dry the organic layer overNa₂SO₄ and concentrate in vacuo. Purify by chromatography on silica geleluting with hexane/EtOAc (9:1) to obtain the title compound as anoff-white waxy solid (550 mg, 75%). MS (ES+) m/z: 434 (M+H)⁺.

Preparation 196-Amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

7-Chloro-6-(4-methoxybenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(15 g, 35.3 mmol), with 4-methoxybenzylamine (13.7 mL, 106 mmol) usingtris(dibenzylideneacetone)-dipalladium(0) (1.62 g, 1.76 mmol), BINAP(4.40 g, 3.5 mmol) and cesium carbonate (16.1 g, 49.4 mmol) at 80° C.for 17 h. Filter the mixture through a pad of Celite® and evaporate thefiltrate. Dissolve the residue in DCM and filter through a pad of silicagel. Evaporate the filtrate and purify by chromatography on silica geleluting with hexane/EtOAc (1:0 to 2:3) to give the desired intermediateas a white solid (12.4 g, 86%). MS (ES+) m/z: 412 (M+H)⁺.6-Amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Treat7-chloro-6-(4-methoxybenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine(5.41 g, 13.1 mmol) with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.59g, 15.8 mmol) in toluene (66 mL) at ambient temperature for 2 h. Dilutethe mixture with EtOAc and wash with saturated aqueous NaHCO₃ (5×100mL). Extract the aqueous layer with ether, combine the organic extractsand evaporate to a volume of 300 mL. Extract the organic phase with 1Naqueous HCl (5×100 mL), and then wash the combined aqueous layers withether (4×75 mL). Cool the aqueous phase to 0° C., neutralize with 5Naqueous NaOH (100 mL), and extract with DCM (5×200 mL). Wash thecombined organic extracts with brine, dry over Na₂SO₄ and evaporate toobtain the title compound as a white solid (3.6 g, 94%). MS (ES+) m/z:293 (M+H)⁺.

Preparation 206-(2-Amino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

6-(2-tert-Butoxycarbonylamino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Use a method similar to the General Procedure 5-1, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(150 mg, 0.352 mmol), palladium(II) acetate (8 mg, 0.0352 mmol), BINAP(22 mg, 0.0352 mmol), cesium carbonate (163 mg, 0.5 mmol), t-butylN-(2-aminoethyl)-carbamate (254 mg, 1.59 mmol) and toluene (6 mL) togive, after chromatography on silica gel eluting with hexane/EtOAc(4:1), the desired intermediate (136 mg, 89%).6-(2-Amino-ethylamino)-7chloro-3-(2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve6-(2-tert-butoxycarbonylamino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(136 mg, 0.31 mmol) in 4M hydrogen chloride in dioxane (20 mL) and stirat ambient temperature for 25 min. Concentrate to afford thehydrochloride salt. Dissolve the salt in DCM and wash with saturatedaqueous NaHCO₃. Extract the basic aqueous layer with DCM, dry theorganic layer over MgSO₄, filter, and concentrate in vacuo to give thetitle compound (64 mg, 62%). MS (ES+) m/z: 336 (M+H)⁺.

Preparation 216-(3-Amino-propylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Use a method similar to the Preparation 20, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(600 mg, 1.41 mmol) and tert-butyl N-(3-aminopropyl)-carbamate (1.11 g,6.34 mmol) to give the title compound (34% overall).

Preparation 227-Chloro-6-(4-hydroxybenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Dissolve7-chloro-6-(4-methoxybenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.667 g) in DCM (40 mL). Add a 1M solution of boron tribromide in DCM(10 mL) at 0° C. Stir the reaction for 12 h and gradually raise to roomtemperature. Quench the reaction with saturated aqueous NaHCO₃ andextract with DCM three times. Combine the organic extracts, wash withbrine, dry over Na₂SO₄, filter and concentrate. Purify by chromatographyon silica gel eluting with EtOAc/hexane (1:3) to give the title compoundas an oil (888 mg). MS (ES+) m/z: 399 (M+1)⁺.

Preparation 237-Chloro-6-(3-chloro-4-hydroxybenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

7-Chloro-6-(3-chloro-4-methoxybenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Use a method similar to General Procedure 5-3, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.277 g, 3.0 mmol) and 3-chloro-4-methoxy-benzylamine (669 mg, 3.9mmol) to give the desired intermediate as a slightly yellow oil (1.554g, 100%).7-Chloro-6-(3-chloro-4-hydroxybenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Use a method similar to Preparation 22, using7-chloro-6-(3-chloro-4-methoxybenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.36 g, 3.0 mmol) to give the title compound as an off-white solid (876mg, 67% yield). MS (ES+) m/z: 433 (M+H)⁺. MS (ES−) m/z: 431 (M−H)⁻.

Preparation 243-(tert-Butoxycarbonyl)-6-(4-carboxy-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Combine7-chloro-6-(4-methoxycarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.4 g, 0.82 mmol), potassium carbonate (4 g, 28.9 mmol), methanol (3mL), water (3 mL) and heat at 50° C. for 2 h. Cool the reaction mixtureto ambient temperature, add saturated aqueous Na₂CO₃ and dilute with DCM(10 mL). Add di-tert-butyl-dicarbonate (2.4 g, 10.9 mmol by portions.Separate the organic layer and extract the aqueous layer with DCM (3×10mL). Combine the organic extracts, dry over anhydrous Na₂SO₄, evaporatethe solvent and purify by chromatography on silica gel eluting with DCMand DCM/methanol (9:1) to give the title compound as a white solid (0.3g, 80%). MS (ES+) m/z: 331 (M+H-Boc)⁺.

Preparation 25 2-Benzyloxyethylamine

(2-Benzyloxyethyl)-carbamic acid tert-butyl ester: Dissolvetert-butyl-N-(2-hydroxyethyl)-carbamate (10 mL, 64.5 mmol) in anhydrousTHY (500 mL) at 0° C. Add sodium hydride (60% in mineral oil, 3.1 g,77.4 mmol) and stir for 30 min at 0° C. Add benzyl bromide (9.2 mL, 77mmol) followed by tetrabutylammonium iodide (3.7 g, 10 mmol) and stir atambient temperature overnight. Quench with water (500 mL), extract withdiethyl ether (3×100 mL), wash the combined organic extracts with brine,dry over MgSO₄, filter, and evaporate to give the desired intermediate(5 g), that was used without further purification.2-Benzyloxyethylamine: Dissolve (2-benzyloxyethyl)-carbamic acidtert-butyl ester (15 g) in DCM (50 mL), add trifluoroacetic acid (20 mL)and stir at 0° C. for 3 h. Concentrate and dissolve the residue in aminimal amount of DCM. Purify by chromatography on silica gel elutingsequentially with hexane/EtOAc (4:1 and 1:1), EtOAc and 2M ammonia inmethanol to give the title compound (8.3 g, 85%).

Preparation 26 (R)-2-Benzyloxy-1-methyl-ethylamine

(R)-3-Benzyloxy-2-(tert-butoxycarbonylamino)-propane: Dissolve(R)-(+)-2-(tert-butoxycarbonylamino)-1-propanol (875 mg, 5 mmol) inanhydrous THF (50 mL). Add sodium hydride (60% in mineral oil, 210 mg,5.2 mmol) and stir at 0° C. for 30 min. Add benzyl bromide (620 μL, 5.2mmol) followed by tetrabutylammonium iodide (20 mg, 0.05 mmol) and stirfor 3 h at ambient temperature. Pour the mixture into water (200 mL),extract with DCM (3×50 mL), wash with brine, dry over MgSO₄, filter andconcentrate. Purify by chromatography on silica gel eluting withhexane/EtOAc (19:1) to give the desired intermediate as a colorless oil(800 mg, 60%).(R)-2-Benzyloxy-1-methyl-ethylamine: Dissolve(R)-3-benzyloxy-2-(tert-butoxycarbonylamino)-propane (800 mg, 3 mmol) inDCM (10 mL), add trifluoroacetic acid (5 mL), and stir at 0° C. for 20min. Evaporate and purify by SCX chromatography to give the titlecompound as a colorless oil (440 mg, 89%). MS (ES+) m/z: 166 (M+H)⁺.

Preparation 27 (R)-2-(4-Fluorobenzyloxy)-1-methyl-ethylamine

(R)-2-(tert-Butoxycarbonylamino)-3-(4-fluorobenzyloxy)-propane: Dissolve(R)-(+)-2-(tert-butoxycarbonylamino)-1-propanol (1.75 mg, 10.5 mmol) inanhydrous THF (50 mL). Add sodium hydride (60% in mineral oil, 480 mg,12 mmol) and stir at 0° C. for 30 min. Add 4-fluorobenzyl bromide (1.5mL, 12 mmol) followed by tetrabutylammonium iodide (370 mg, 0.1 mmol)and stir for 72 h at ambient temperature. Pour the mixture into water(500 mL), extract with DCM (3×150 mL), wash with brine, dry over MgSO₄,filter and concentrate in vacuo. Purify by chromatography on silica geleluting with hexane/EtOAc (9:1) to give the desired intermediate as ayellow oil (2.18 g, 77%).(R)-2-(4-Fluorobenzyloxy)-1-methyl-ethylamine:Dissolve-(R)-2-(tert-butoxycarbonylamino)-3-(4-fluorobenzyloxy)-propane(2.18 g, 7.7 mmol) in DCM (50 mL), add trifluoroacetic acid (25 mL), andstir at 0° C. for 20 min. Evaporate and purify by SCX chromatography togive the title compound as a colorless oil (1.2 g, 85%). MS (ES+) m/z:184 (M+H)⁺.

Preparation 28 (R)-1-Methyl-2-phenoxy-ethylamine

(R)-2-(tert-Butoxycarbonylamino)-3-phenoxy-propane: Dissolve(R)-(+)-2-(tert-butoxycarbonylamino)-1-propanol (1.75 g, 10 mmol) andphenol (0.95 g, 10 mmol) in anhydrous THF (75 mL). Cool to 0° C., addtriphenylphosphine (4.0 g, 15 mmol) and diisopropylazodicarboxylatedropwise and stir at ambient temperature for 18 h. Pour the mixture intowater (300 mL), basify to pH 10 with 5N aqueous NaOH, and extract withethyl ether (3×100 mL). Wash the organic phase with brine, dry overMgSO₄, filter and concentrate. Purify by chromatography on silica geleluting with hexane/EtOAc (9:1) to give the desired intermediate as anoff-white solid (340 mg, 14%).(R)-1-Methyl-2-phenoxy-ethylamine: Dissolve(R)-2-(tert-butoxycarbonylamino)-3-phenoxy-propane (340 mg, 1.35 mmol)in DCM (80 mL), add trifluoroacetic acid (35 mL), and stir at 0° C. for2 h. Evaporate and purify by SCX chromatography to give the titlecompound as a colorless oil (186 mg, 91%). MS (ES+) m/z: 151 (M+H)⁺.

Preparation 29 4-(Aminomethyl)-2-methyl-thiazole

4-(Azidomethyl)-2-methyl-thiazole: Dissolve4-(chloromethyl)-2-methyl-thiazole (350 mg, 2.37 mmol) andazidotrimethylsilane (315 μL, 2.37 mmol) in anhydrous THF (1 mL) undernitrogen. Add a 1M solution of tetrabutylammonium fluoride (3.6 mL, 3.56mmol) in THF and stir at ambient temperature overnight. Pour thereaction mixture into water (10 mL), extract with ethyl ether (3×2 mL),wash the organic extra with brine, dry over MgSO₄, filter, andevaporate. Purify by chromatography on silica gel eluting withhexane/EtOAc (9:1) to give the desired intermediate as a colorless oil(165 mg, 45%).4-(Aminomethyl)-2-methyl-thiazole: Add 4-(azidomethyl)-2-methyl-thiazole(165 mg, 1.07 mmol) to a slurry of methanol containing 10% Pd/C (75 mg)and stir vigorously under 1 atm H₂ for 1 h. Filter, evaporate thesolvent, and purify by SCX chromatography to give the title compound (55mg, 40%).

Preparation 30 2-Fluoro-4-phenoxy-benzylamine

(4-Bromo-2-fluorobenzyl)-carbamic acid tert-butyl ester: Mix undernitrogen 4-bromo-2-fluorobenzylamine hydrochloride (7.2 g, 30 mmol),di-tert-butyl-dicarbonate (9.8 g, 45 mmol), and potassium carbonate(12.4 g, 90 mmol) in anhydrous THF (200 mL). Stir at ambient temperaturefor 16 h. Filter and concentrate in vacuo. Purify by chromatography onsilica gel eluting with hexane/EtOAc (9:1) to obtain the desiredintermediate (6.4 g, 70%). GC-MS m/z: 247 [(M-C₄H₉)⁺].(2-Fluoro-4-phenoxy-benzyl)-carbamic acid tert-butyl ester: Mix underargon atmosphere (4-bromo-2-fluorobenzyl)-carbamic acid tert-butyl ester(2.12 g, 7.0 mmol), phenol (1.32 g, 14 mmol),2,2,6,6-tetramethylheptane-3,5-dione (129 mg, 0.7 mmol), and cesiumcarbonate (4.56 g, 14 mmol) in anhydrous NMP (15 mL). Degas the flask,fill with argon and add copper(I) chloride (346 mg, 3.5 mmol) quickly.Degas the flask then fill with argon and heat at 120° C. for 5 h. Coolto ambient temperature, dilute with EtOAc and filter. Wash the mixturesequentially with 0.5N aqueous HCl, 0.5N aqueous NaOH and brine.Separate the organic layer, dry over Na₂SO₄ and concentrate in vacuo.Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0,9:1 and 3:1) to obtain the desired intermediate (1.28 g, 58%). GC-MSm/z: 260 [(M-C₄H₉)⁺].2-Fluoro-4-phenoxy-benzylamine: Dissolve(2-fluoro-4-phenoxy-benzyl)-carbamic acid tert-butyl ester (2.44 g, 7.72mmol) in DCM (200 mL). Add trifluoroacetic acid (50 mL) then stir atambient temperature for 16 h. Evaporate the solvent, dissolve theresidue in DCM and wash with 1N aqueous NaOH. Dry over Na₂SO₄ andconcentrate in vacuo. Purify by SCX chromatography to obtain the titlecompound (557 mg, 33%). MS (ES+) m/z: 201 (M+H—NH₃)⁺.

Preparation 31 2-Fluoro-4-(3′-fluorophenoxy)-benzylamine

Use a method similar to Preparation 30, using(4-bromo-2-fluorobenzyl)-carbamic acid tert-butyl ester (2.12 g, 7.0mmol) and m-fluorophenol (1.57 g, 14 mmol) to give the title compound(468 mg, 47% overall).

Preparation 32 4-2′-Fluorophenoxy)-benzylamine

4-(2′-Fluorophenoxy)-benzonitrile: Mix under argon atmosphere4-bromobenzonitrile (2.0 g, 11.3 mmol), 2-fluorophenol (2.5 g, 22.6mmol), 2,2,6,6-tetramethylheptane-3,5-dione (203 mg, 1.1 mmol), andcesium carbonate (7.4 g, 22.6 mmol) in anhydrous NMP (19 mL). Degas theflask, fill with argon and add copper(I) chloride (554 mg, 5.6 mmol)quickly. Degas the flask then fill with argon and heat at 120° C. for 3h. Cool to ambient temperature, dilute with EtOAc, filter and wash thefiltrate sequentially with 2M aqueous HCl, 0.3M aqueous HCl, 2M aqueousNaOH and brine. Separate the organic layer, dry over Na₂SO₄ andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate (1.6g, 66%). MS (ES+) m/z: 231 (M+NH₄)⁺.4-(2′-Fluorophenoxy)-benzylamine: Add 4-(2′-fluorophenoxy)-benzonitrile(1.5 g, 7.0 mmol) and ethanol wet Raney® activated nickel (0.4 g) to aParr pressure vessel. Immediately add a 7N solution of ammonia inmethanol (170 mL) and seal the vessel. Purge the reaction vessel withnitrogen, pressurize the reaction mixture with hydrogen (3400 KPa), sealthe vessel, agitate the reaction and heat to 60° C. Continue thereaction for 18 h, turn off the heat and allow the reaction mixture tocool to ambient temperature. Vent the excess hydrogen from the vesseland purge the vessel with nitrogen. Filter the reaction mixture toremove the Raney® nickel. Concentrate in vacuo and purify bychromatography on silica gel eluting with DCM/2M ammonia in methanol(9:1) to obtain the title compound (1.2 g, 79%). MS (ES+) m/z: 201(M+H—NH₃)⁺.

The compound of Preparation 33 may be prepared essentially as describedin Preparation 32 using 4-bromobenzonitrile and 3-fluorophenol. Overallyield and MS (ES+) data are shown in the Table below.

Yield MS (ES+) Prep. Compound (%) m/z 334-(3′-Fluorophenoxy)-benzylamine 53 201 (M + H − NH₃)⁺

Preparation 34 4-(3′-Isopropylphenoxy)-benzylamine

Use a method similar to Preparation 32 (Step 1), using4-bromobenzonitrile (2.0 g, 11.3 mmol) and 3-isopropylphenol (3.08 g,22.6 mmol) to give 4-(3′-isopropylphenoxy)-benzonitrile (885 mg, 33%).MS (ES+) m/z: 255 (M+NH₄)⁺.

Use a method similar to the reduction procedure described in Preparation45 (Step 2), using 4-(3′-isopropylphenoxy)-benzonitrile (875 mg, 3.7mmol) to give the title compound (703 mg, 79%). MS (ES+) m/z: 225(M+H—NH₃)⁺.

The compounds of Preparations 35-39 may be prepared essentially asdescribed in Preparation 34 by using 4-bromobenzonitrile and theappropriate phenol. Overall yields and MS (ES+) data are shown in theTable below.

Yield MS (ES+) Prep. Compound (%) m/z 35 4-(2′-Isopropylphenoxy)- 28 225(M + H − NH₃)⁺ benzylamine 36 4-(3′-Methylphenoxy)-benzylamine 60 197(M + H − NH₃)⁺ 37 4-(2′-Methylphenoxy)-benzylamine 59 197 (M + H − NH₃)⁺38 4-(3′,5′-Difluorophenoxy)- 24 219 (M + H − NH₃)⁺ benzylamine 394-(3′-Chlorophenoxy)-benzylamine 44 217 (M + H − NH₃)⁺

Preparation 40 2-(4-Aminomethyl-phenoxy)-benzonitrile

(4-Hydroxybenzyl)-carbamic acid tert-butyl ester: Mix2,2,2-trifluoro-N-(4-hydroxybenzyl)-acetamide (8.8 g, 40 mmol), and 5Naqueous NaOH (20 mL) in methanol (100 mL). Stir at ambient temperaturefor 4 h. Adjust pH to about 8 with aqueous HCl. Add solid sodiumbicarbonate (4.4 g, 52 mmol), di-tert-butyl-dicarbonate (9.3 g, 40 mmol)and DCM. Stir at ambient temperature for 16 h. Dilute with DCM, washwith 1N aqueous HCl and purify by chromatography on silica gel elutingwith hexane/EtOAc (9:1 to 5:5) to obtain the desired intermediate (7.8g, 87%). MS (ES−) m/z: 222 (M−H)⁻.2-(4-Aminomethyl-phenoxy)-benzonitrile: Mix under argon(4-hydroxybenzyl)-carbamic acid tert-butyl ester (1.5 g, 6.7 mmol),2-bromobenzonitrile (813 mg, 4.5 mmol),2,2,6,6-tetramethylheptane-3,5-dione (83 mg, 0.45 mmol), and cesiumcarbonate (2.2 g, 6.7 mmol) in anhydrous NMP (8.5 mL). Degas the flaskand fill with argon. Add copper(I) chloride (223 mg, 2.25 mmol) quickly.Degas the flask, fill with argon and heat at 120° C. for 3 h. Cool toambient temperature, dilute with EtOAc, filter and concentrate in vacuo.Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0,9:1 and 3:1). Evaporate the solvent and dissolve the residue in DCM (100mL). Add trifluoroacetic acid (20 mL) and stir at ambient temperaturefor 16 h. Concentrate in vacuo, dissolve the residue in EtOAc and washwith 1N aqueous NaOH. Dry over Na₂SO₄ and concentrate in vacuo. Purifyby SCX chromatography to obtain the title compound (385 mg, 38%). MS(ES+) m/z: 225 (M+H)⁺.

The compounds of Preparation 4143 may be prepared essentially asdescribed in Preparation 40 by using (4-hydroxybenzyl)-carbamic acidtert-butyl ester (1.5 g, 6.7 mmol) and the appropriate bromide. Overallyields and MS (ES+) data are shown in the Table below.

Yield MS (ES+) Prep. Compound (%) m/z 41 4-(2′-Trifluoromethyl-phenoxy)-13 251 (M + H − NH₃)⁺ benzylamine 2 4-(3′-Trifluoromethyl-phenoxy)- 27251 (M + H − NH₃)⁺ benzylamine 43 4-(Pyridin-3-yloxy)-benzylamine 11 201(M + H)⁺

Preparation 44 3-(4-Aminomethyl-phenoxy)-benzonitrile

Use a method similar to Preparation 40 (Step 2), using2,2,2-trifluoro-N-(4-hydroxybenzyl)-acetamide (1.0 g, 5.5 mmol) and3-bromobenzonitrile (673 mg, 3.7° mmol). Purify by chromatography onsilica gel eluting with hexane/EtOAc (1:0 and 3:1). Concentrate invacuo. Dissolve the residue (287 mg, 0.89 mmol) in methanol (25 mL) andadd 5N NaOH (7 mL). Stir at room temperature for 4 h. Dilute with DCMand add solid sodium chloride to the mixture. Extract the aqueous layerthree times with DCM. Combine organic extracts, dry over Na₂SO₄ andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith DCM/2M ammonia in methanol (94:6) to obtain the title compound (124mg, 62%). MS (ES+) m/z: 500 (M+H)⁺.

Preparation 45 4-(3,3-Dimethylbutoxy)-benzylamine

4-(3,3-Dimethylbutoxy)-benzonitrile: Mix 4-cyanophenol (1.2 g, 10 mmol),1-bromo-3,3-dimethylbutane (5.3 g, 32 mmol), powdered potassiumcarbonate (4.14 g, 30 mmol), and powdered potassium iodide (166 mg, 1mmol) in acetone (60 mL). Stir under inert atmosphere and heat at refluxfor 48 h. Cool the reaction mixture to ambient temperature. Dilute withacetone, filter and evaporate. Purify by chromatography on silica geleluting with hexane/EtOAc (10 and 9:1) to obtain the desiredintermediate (1.8 g, 89%). MS (ES+) m/z: 221 (M+NH₄)⁺.4-(3,3-Dimethylbutoxy)-benzylamine: Mix lithium aluminum hydride (1.0 g,26.6 mmol) and anhydrous ethyl ether (70 mL) under nitrogen atmosphere.Stir and cool to 0° C. in an ice bath. Add dropwise a solution of4-(3,3-dimethylbutoxy)-benzonitrile (1.8 g, 8.87 mmol) in anhydrousethyl ether (20 mL). Stir for 2 h at 0° C., remove the ice bath and stirat ambient temperature for 18 h. Cool the reaction flask in an ice bathand add carefully dropwise and sequentially water (1 mL), 2N aqueousNaOH (1 mL), and water (2 mL). Stir for 30 min. filter, separate theorganic layer, dry over Na₂SO₄ and concentrate in vacuo to obtain thetitle compound (1.62 g, 88%). MS (ES+) m/z: 191 (M+H—NH₃)⁺.

The compounds of Preparations 4648 may be prepared essentially asdescribed in Preparation 45 by using 4-cyanophenol and the appropriatebromide. Overall yields and MS (ES+) data are shown in the Table below.

Yield MS (ES+) Prep. Compound (%) m/z 46 4-Cyclohexylmethoxy-benzylamine90 203 (M + H − NH₃)⁺ 47 4-(2-Cyclohexylethoxy)- 94 217 (M + H − NH₃)⁺benzylamine 48 4-(2,2-Dimethylpropoxy)- 4 177 (M + H − NH₃)⁺ benzylamine

Preparation 49 4-Benzyloxy-benzylamine

4-Benzyloxy-benzonitrile: Add 4-cyanophenol (1.191 g, 10 mmol), benzylbromide (1.881 g, 11 mmol), potassium carbonate (3.455 g, 25 mmol) andpotassium iodide (166 mg, 1 mmol) to acetonitrile (80 mL) and heat atreflux for 12 h. Cool, partition between EtOAc and water, separate heorganic layer, and extract the aqueous layer with EtOAc. Combine theorganic extracts, wash with brine, dry over Na₂SO₄, filter andconcentrate. Purify by chromatography on silica gel eluting withEtOAc/hexane (1:6) to give the desired intermediate as a white solid(2.098 g, 100%). MS (ES+) m/z: 227 (M+NH₄)⁺.4-Benzyloxy-benzylamine: Use a method similar to Preparation 58, using4-benzyloxy-benzonitrile (2.098 g, 10 mmol), to give the title compoundas a white solid (2.021 g, 94%). MS (ES+) m/z: 197 (M+H—NH₃)⁺.

Preparation 50 (±)-4-(1-Phenylethoxy)-benzylamine

(±)-4-(1-Phenylethoxy)-benzonitrile: Add triphenylphosphine (7.869 g, 30mmol) to a solution of sec-phenylethyl alcohol (1.467 g, 12 mmol),4-cyanophenol (1.191 g, 10 mmol) and diethyl azodicarboxylate (4.528 g,26 mmol) in anhydrous THF (50 mL) at 0° C. Stir the reaction at ambienttemperature for 12 h. Dilute with EtOAc, wash with brine, dry overNa₂SO₄, filter and concentrate. Purify by chromatography on silica geleluting with EtOAc/hexane (1:8) to give(±)-4-(1-phenylethoxy)-benzonitrile with a small amount oftriphenylphosphine (2.49 g total).(±)-4-(1-Phenylethoxy)-benzylamine: Use a method similar to Preparation58, using crude (±)-4-(1-phenylethoxy)-benzonitrile, to give the titlecompound as a colorless oil (1.6 g, 70% two steps). MS (ES+) m/z: 211(M+H—NH₃)⁺, 455.3 (2M+H)⁺.

Preparation 51 4-(3,3-Dimethyl-2-oxo-butoxy)-benzylamine

2,2,2-Trifluoro-N-(4-methoxybenzyl)acetamide: Mix under nitrogenatmosphere 4-methoxybenzylamine (13.7 g, 100 mmol) andN-methylmorpholine in anhydrous THF (300 mL). Cool to 0° C. in an icebath. Add dropwise a solution of trifluoroacetic anhydride (15.6 mL, 110mmol) in anhydrous THF (25 mL). Warm up to ambient temperature slowlyand stir for 16 h. Concentrate in vacuo. Dissolve in EtOAc and washsuccessively with 1N aqueous NaOH, 1N aqueous HCl, and brine. Separatethe organic layer, dry over Na₂SO₄ and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (9:1 and 4:1) toobtain the desired intermediate (19 g, 81%). MS (ES−) m/z: 232 (M−H)⁻.2,2,2-Trifluoro-N-(4-hydroxy-benzyl)-acetamide: Dissolve under nitrogenatmosphere 2,2,2-trifluoro-N-(4-methoxybenzyl)-acetamide (11.6 g, 50mmol) in DCM (250 mL). Cool to 0° C. in an ice bath. Add dropwise 1Mboron tribromide in DCM (100 mL, 100 mmol) and stir for 20 min afteraddition. Warm to ambient temperature and stir for 16 h. Cool thereaction mixture in an ice bath and quench very carefully with saturatedaqueous NaHCO₃. Separate the organic layer. Extract the aqueous layertwice with chloroform. Dry the combined organic extracts over-Na₂SO₄ andconcentrate in vacuo to obtain the desired intermediate (8.8 g, 40mmol). MS (ES−) m/z: 218 (M−H)⁻.N-[4-(3,3-Dimethyl-2-oxo-butoxy)-benzyl]-2,2,2-trifluoroacetamide: Mix2,2,2-trifluoro-N-(4-hydroxy-benzyl)-acetamide (438 mg, 2.0 mmol),1-bromopinacolone (430 mg, 2.4 mmol), anhydrous potassium carbonate (829mg, 6.0 mmol) and potassium iodide (33 mg, 0.1 mmol) with acetone. Heatunder reflux for 12 h. Acidify with 1N aqueous HCl and extract withEtOAc three times. Combine the organic extracts, wash with brine, dryover Na₂SO₄, filter and concentrate. Purify by chromatography on silicagel eluting with EtOAc/hexane (1:3) to give the desired intermediate asa colorless oil. MS (ES+) m/z: 335 (M+NH₄)⁺. MS (ES−) m/z: 316 (M−H)⁻.4-(3,3-Dimethyl-2-oxo-butoxy)-benzylamine: Add 5N aqueous NaOH (15 mL)to a solution ofN-[4-(3,3-dimethyl-2-oxo-butoxy)-benzyl]-2,2,2-trifluoro-acetamide (552mg, 1.74 mmol) in methanol (0 mL) and stir for 2 h at ambienttemperature. Extract the mixture with DCM three times. Dry the combinedorganic extracts over Na₂SO₄, filter and concentrate. Purify bychromatography on silica gel eluting with DCM/2M ammonia in methanol(92:8) to give the title compound as a colorless oil (337 mg, 87%). MS(ES+) m/z: 205 (M+H—NH₃)⁺.

Preparation 52 N-(2-Chloro-acetyl)-piperidine

Add chloroacetyl chloride (1.242 g, 11.0 mmol) to a mixture of potassiumcarbonate (2.073 g, 15 mmol) and piperidine (852 mg, 10 mmol) in THF (50mL) at 0° C. Stir the reaction for 12 h and gradually raise to roomtemperature. Dilute with water, extract with EtOAc three times. Combinethe organic extracts and wash sequentially with saturated aqueousNaHCO₃, 0.1N aqueous HCl and brine. Dry over Na₂SO₄, filter andconcentrate to give the title compound (1.65 g, 100%).

Preparation 53 4-Benzylthio-benzylamine

4-Benzylthio-benzonitrile: Mix under argon atmosphere4-fluorobenzonitrile (1.21 g, 10 mmol), benzyl mercaptan (1.86 g, 15mmol), and cesium carbonate (6.5 g, 20 mmol) in anhydrous NMP (20 mL).Degas the flask and fill with argon. Heat at 120° C. for 3 h. Cool toambient temperature, dilute with EtOAc, filter and wash with 1N aqueousHCl. Separate the organic layer, dry over Na₂SO₄ and concentrate invacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc(1:0 and 9:1) to obtain the desired intermediate (689 mg, 31%). GC-MSm/z: 225 (M⁺).4-Benzylthio-benzylamine: Use the reduction procedure described inPreparation 45 (Step 2), using 4-benzylthio-benzonitrile (689 mg, 3.1mmol) to give, after SCX chromatography, the title compound (464 mg,64%). MS (ES+) m/z: 213 (M+H—NH₃)⁺.

Preparation 54 4-(2,2,3,3,3-Pentafluoropropoxy)-benzylamine

4-(2,2,3,3,3-Pentafluoropropoxy)-benzonitrile: Heat a mixture of4-hydroxy-benzonitrile potassium fluoride complex (3.0 g, 16.9 mmol) and1,1,1,2,2-pentafluoro-3-iodo-propane (10.8 g, 37.2 mmol) in DMSO (80 mL)to 130° C. for 20 h. Cool the mixture to ambient temperature, dilutewith hexane/EtOAc (1:1, 200 mL) and wash with aqueous 10% NaCl (3×50mL). Dry the organic layer, concentrate in vacuo and purify bychromatography on silica gel eluting with hexane/EtOAc (10:1, 10:2 and10:3) to obtain the desired intermediate (1.1 g, 26%). GC-MS m/z: 251(M⁺).4-(2,2,3,3,3-Pentafluoropropoxy)-benzylamine: Use a method similar tothe General Procedure 64, using4-(2,2,3,3,3-pentafluoropropoxy)-benzonitrile (1.1 g, 4.1 mmol), toobtain the title compound (1.1 g, 99%). GC-MS m/z: 254 (M⁺−H).

Preparation 55 4-(2,2,3,3-Tetrafluoropropoxy)-benzylamine

Use a method similar to Preparation 54, using 4-hydroxy-benzonitrilepotassium fluoride complex (4.2 g, 23.7 mmol) and1,1,2,2-tetrafluoro-3-iodo-propane (10 g, 41.3 mmol), to give the titlecompound (38% overall). GC-MS m/z: 236 (M⁺−H).

Preparation 56 4-(2,2,2-Trifluoro-1,1-dimethyl-ethoxy)-benzylamine

4-(2,2,2-Trifluoro-1,1-dimethyl-ethoxy)-benzonitrile: Add2-trifluoromethyl-2-propanol (3.4 g, 27 mmol) slowly to a slurry ofsodium hydride (0.6 g, 60% in mineral oil, washed with hexane) in HMPA(5 mL) under nitrogen. Stir the slurry for 15 min and add a solution of4-nitrobenzonitrile (2.0 g, 13.5 mmol) in HMPA (10 mL). Stir theresulting purple slurry at ambient temperature for 16 h, dilute withdiethyl ether (100 mL) and wash with 5% aqueous HCl (30 mL). Separatethe layers and extract the aqueous layer with diethyl ether (2×50 mL).Combine the organic extracts and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) toobtain the desired intermediate (780 mg, 25%). GC-MS m/z: 229 (M⁺).4-(2,2,2-Trifluoro-1,1-dimethyl-ethoxy)-benzylamine: Use a methodsimilar to the General Procedure 64 to reduce4-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-benzonitrile (780 mg, 3.4 mmol).Purify by chromatography on silica gel eluting with DCM/2M ammonia inmethanol (40:1, 20:1 and 10:1) to obtain the title compound (780 mg,98%). GC-MS m/z: 232 (M⁺−H).

Preparation 57 (±)-4-(2,2,2-Trifluoro-1-methyl-ethoxy)-benzylamine

(±)-4-(2,2,2-Trifluoro-1-methyl-ethoxy)-benzonitrile: Add1,1,1-trifluoro-2-propanol (3.8 g, 66 mmol) slowly to a slurry of sodiumhydride (730 mg, 60% in mineral oil, washed with hexane) in HMPA (5 mL)under nitrogen. Stir the slurry for 15 min and add 4-fluorobenzonitrile(2 g, 16.5 mmol). Heat the slurry in a sealed flask to 90° C. for 16 h.Cool the mixture to ambient temperature and pour the mixture into aflask containing 5% aqueous HCl (20 mL). Extract the mixture withdiethyl ether (3×50 mL), and wash with 5% aqueous HCl (25 mL). Dry theorganic layer over Na₂SO₄ and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (9:1) to obtainthe desired intermediate (2.5 g, 70%). GC-MS m/z: 215 (M⁺).(±)-4-(2,2,2-Trifluoro-1-methyl-ethoxy)-benzylamine: Use a methodsimilar to the General Procedure 6-4, using(±)-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzonitrile (1.0 g, 4.6 mmol),to obtain the title compound (1.1 g, 95%). GC-MS m/z: 218 (M+H)⁺.

Preparation 58 3-Methoxybenzylamine

Add lithium aluminum hydride (3.795 g, 100 mmol) portion wise to asolution of 3-methoxybenzonitrile (5.326 g, 40 mmol) in anhydrous ethylether (200 mL) at 0° C. Stir for 1 h, warm to ambient temperature andcontinue to stir for 12 h. Quench the reaction with 0.1N aqueous NaOH,filter the solid, dry the filtrate over Na₂SO₄ and concentrate to givethe title compound as a colorless oil (5.107 g, 93%). MS (ES+) m/z: 138(M+H)⁺.

Preparation 59 3-(tert-Butyl)benzylamine

Dissolve 3-tert-butyltoluene (0.5 mL, 2.9 mmol) in carbon tetrachloride(20 mL). Add NBS (530 mg, 3 mmol) and irradiate the reaction mixturewith a 250 watt sun-lamp with simultaneous heating to reflux for 1 h.Cool to ambient temperature, filter, and concentrate filtrate to drynessto give crude 1-bromomethyl-3-tert-butylbenzene. Dissolve crude1-bromomethyl-3-tert-butylbenzene (600 mg) in anhydrous DMF. Add portionwise sodium azide (260 mg, 4 mmol) and stir at room temperature for 2 h.Pour the mixture into water (250 mL), extract with EtOAc (3×50 mL), washcombined organic extracts with brine, dry over MgSO₄, filter andevaporate solvent to give crude 1-azidomethyl-3-tert-butylbenzene, thatwas used without further purification. Dissolve crude1-azidomethyl-3-tert-butylbenzene in methanol containing 10% Pd/C (75mg) at 5° C., and stir the resulting slurry under 1 atm H₂ for 1 h.Filtrate, concentrate in vacuo and purify by chromatography on silicagel eluting sequentially with hexane/EtOAc (4:1 and 1:1), EtOAc,methanol and 2M ammonia in methanol to give the title compound (255 mg,53% overall). MS (ES+) m/z: 164 (M+H)⁺.

Preparation 60 (3-Pyrrolidin-1-yl)benzylamine

Slurry a mixture of (3-bromobenzyl)-carbamic acid tert-butyl ester (600mg, 2.1 mmol, U.S. Pat. Appl. Publ. US 2003134885), pyrrolidine (450 mL,5.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (200 mg, 0.21 mmol),BINAP (400 mg, 0.63 mmol) and cesium carbonate (960 mg, 2.94 mmol) inanhydrous toluene (10 mL). Degas under vacuum, fill the system withnitrogen and heat in a sealed flask at 90° C. for 18 h. Cool to roomtemperature, dilute with diethyl ether, filter, and concentrate invacuo. Dissolve the resulting residue in DCM (10 mL) and addtrifluoroacetic acid (5 mL). Stir at ambient temperature for 1 h andconcentrate in vacuo. Purify by chromatography on silica gel elutingsequentially with hexane/EtOAc (1:1), EtOAc and 2M ammonia in methanol.Purify again by SCX chromatography to give the title compound as a brownoil (300 mg, 85% overall). MS (ES+) m/z: 178 (M+H)⁺.

Preparation 61 (±)-C-(3-Methyl-2,3-dihydro-benzofuran-5-yl)-methylamine

4-Allyloxy-3-bromo-benzonitrile: Mix 3-bromo-4-hydroxy-benzonitrile(1.520 g, 8.0 mmol), alkyl bromide (1.161 g, 9.6 mmol), potassiumcarbonate (3.317 g, 24 mmol) and potassium iodide (133 mg, 0.1 mmol) inacetone (80 mL). Heat the mixture to reflux for 12 h. Cool to ambienttemperature, add EtOAc, wash the organic layer with water, and extractthe aqueous layer twice with EtOAc. Dry the combined organic extractsover Na₂SO₄, filter and concentrate. Purify by chromatography on silicagel eluting with EtOAc/hexane (1:8) to obtain the desired intermediate.(±)-3-Methyl-2,3-dihydro-benzofuran-5-carbonitrile: Add tri-n-butyltinhydride (5.821 g, 20 mmol) and AIBN (411 mg, 2.5 mmol) to a solution of4-alkyloxy-3-bromo-benzonitrile (595 mg, 2.5 mmol). Heat the reaction atreflux for 20 h. Dilute with EtOAc and wash with water. Extract theaqueous layer with EtOAc three times. Combine the organic extracts, washwith brine, dry over Na₂SO₄, filter and concentrate in vacuo. Purify bychromatography on silica gel eluting with EtOAc/hexane (1:8) to give thedesired intermediate as a white solid (474 mg, 100% with a trace amountof tributyltin derivative).(±)-C-(3-Methyl-2,3-dihydro-benzofuran-5-yl)-methylamine: Use a methodsimilar to Preparation 58, using(±)-3-methyl-2,3-dihydro-benzofuran-5-carbonitrile (474 mg, 2.98 mmol)to give the title compound as a colorless oil (410 mg, 84%).

The compounds of Preparations 62-64 may be prepared essentially asdescribed in Preparation 61 by using 3-bromo-4-hydroxy-benzonitrile or4-bromo-3-hydroxy-benzonitrile and the appropriately substituted alkylbromide. MS (ES+) data are shown in the Table below.

MS (ES+) Prep. Structure Compound m/z 62

(±)-C-(3-Methyl-2,3-dihydro-benzofuran-6-yl)-methylamine 164(M + H)⁺ 63

C-(3,3-Dimethyl-2,3-dihydro-benzofuran-5-yl)-methylamine ND 64

C-(3,3-Dimethyl-2,3-dihydro-benzofuran-6-yl)-methylamine 178(M + H)⁺ ND= Not determined

Preparation 65C-(2,2-Dimethyl-3-oxo-2,3-dihydro-benzofuran-5-yl)-methylamine

N-(2,2-Dimethyl-3-oxo-2,3-dihydro-benzofuran-5-ylmethyl)-2,2,2-trifluoro-acetamide:Add 2-bromoisobutyryl bromide (1.724 g, 7.5 mmol) to a solution of2,2,2-trifluoro-N-(4-methoxy-benzyl)-acetamide (1.166 g, 5.0 mmol) in1,2-dichloroethane (8 mL) at 15° C., then add powdered anhydrousiron(III) chloride (973 mg, 6.0 mmol). Stir the reaction at 15° C. for 3h and at ambient temperature for 8 days. Add dropwise saturated aqueouspotassium sodium tartrate, then water and EtOAc, and stir for 1 h.Filter off the solid, separate the organic layer, and extract theaqueous layer three times with EtOAc. Combine the organic extracts, washwith brine, dry over Na₂SO₄, filter and concentrate in vacuo. Purify bychromatography on silica gel eluting with EtOAc/hexane (1:3) to give thedesired intermediate (253 mg, 17%).C-(2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-5-yl)-methylamine: DissolveN-(2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-5-ylmethyl)-2,2,2-trifluoro-acetamide(253 mg, 0.88 mmol) in 7M ammonia in methanol and stir at ambienttemperature for 5 days. Remove volatiles in vacuo, purify bychromatography on silica gel eluting with DCM/2M ammonia in methanol(92:8) to give the title compound (44 mg, 26%). MS (ES+) m/z: 175(M+H—NH₃)⁺.

Preparation 66C-(2,2-Dimethyl-3-oxo-2,3-dihydro-benzofuran-6-yl)-methylamine

2,2,2-Trifluoro-N-(3-methoxy-benzyl)-acetamide: Add trifluoroaceticanhydride (6.3 g, 30 mmol) to a solution of 3-methoxybenzylamine (3.43g, 25 mmol) and N-methyl-morpholine (3.793 g, 37.5 mmol) in THF (80 mL)at 0° C. and stir at this temperature for 4 h. Warm to ambienttemperature and stir for 12 h. Dilute with EtOAc, wash sequentially withwater, 1N aqueous HCl, saturated aqueous NaHCO₃ and brine. Dry theorganic layer over Na₂SO₄, filter and concentrate. Purify bychromatography on silica gel eluting with EtOAc/hexane (1:3) to give thedesired intermediate (5.344 g, 91%).C-(2,2-Dimethyl-3-oxo-2,3-dihydro-benzofuran-6-yl)-methylamine: Use amethod similar to Preparation 65, using2,2,2-trifluoro-N-(3-methoxy-benzyl)-acetamide (1.166 g, 5 mmol), togive the title compound (220 mg, 23% two steps). MS (ES+) m/z: 192(M+H)⁺.

Preparation 67 6-Aminomethyl-2,2-dimethyl-2H-chromene

Add 2,2-dimethyl-2H-chromene-6-carbonitrile (1.5 g, 8.1 mmol) andethanol wet Raney® activated nickel (0.4 g) to a Parr pressure vessel.Immediately add 7N ammonia in methanol (170 mL) and seal the vessel.Purge the reaction vessel with nitrogen, pressurize the reaction mixturewith hydrogen (3400 KPa), seal the vessel, agitate the reaction and heatto 60° C. for 20 h. Turn off the heat and allow the reaction mixture tocool to ambient temperature. Vent the excess hydrogen from the vesseland purge the vessel with nitrogen. Filter the reaction mixture toremove the Raney® nickel. Purify by chromatography on silica gel elutingwith DCM/2M ammonia in methanol (9:1) to obtain the title compound (1.5g, 97%). MS (ES+) m/z: 175 (M+H—NH₃)⁺.

Preparation 68 4-(2-Methylthiazol-4-yl)-benzylamine

4-(2-Methylthiazol-4-yl)-benzonitrile: Suspend 4-cyanophenacyl bromide(515 mg, 2.23 mmol) in ethanol (15 mL). Add thioacetamide (171 mg, 2.23mmol) and sodium bicarbonate (187 mg, 2.23 mmol) and heat the mixtureunder reflux for 2 h. Concentrate in vacuo and dissolve the residue inDCM. Wash the organic fraction with water, dry over Na₂SO₄, filter andconcentrate to give a solid. Suspend the solid in ether/hexane andfilter under vacuum washing with hexane to obtain the desiredintermediate as a white solid (415 mg, 93%). GC-MS m/z: 200 (M⁺).442-Methylthiazol-4-yl)-benzylamine: Dissolve4-(2-methylthiazol-4-yl)-benzonitrile (305 mg, 1.52 mmol) in anhydrousTHF (50 mL). Add a 1M solution of lithium aluminum hydride in THF (3.05mL, 3.05 mmol). Heat the mixture overnight under reflux. Cool thereaction mixture with ice/water and work-up sequentially with EtOAc andwater. Filter the mixture over Celite®. Separate the organic phase, andextract the aqueous phase with chloroform. Dry the combined organicextracts over Na₂SO₄, filter and concentrate to obtain the titlecompound as an oil (120 mg) that was used without further purification.GC-MS m/z: 204

Preparation 69 4-(Pyridin-4-yl)-benzylamine

N-(tert-Butoxycarbonyl)-4-bromo-benzylamine: Adddi-tert-butyl-dicarbonate (1.173 g, 5.375 mmol) and triethylamine (1.087g, 1.0 mL, 10.75 mmol) to a stirred solution of 4-bromobenzylamine (1.0g, 5.375 mmol) in anhydrous DCM (15 mL). Stir overnight at ambienttemperature, dilute with DCM and wash with water. Separate the organicphase, dry over Na₂SO₄, filter and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (1:0, 19:1 and9:1) to obtain the desired intermediate as a solid (1.24 g, 81%).N-(tert-Butoxycarbonyl)-4-(Pyridin-4-yl)-benzylamine: DissolveN-(tert-butoxycarbonyl)-4-bromo-benzylamine (0.8 g, 2.807 mmol) inanhydrous DME (12 mL) under nitrogen. Addtetrakis(triphenylphosphine)palladium(0) (0.162 g, 0.14 mmol),pyridine-4-boronic acid (0.513 g, 4.211 mmol), and a 2M aqueous Na₂CO₃solution (2.8 mL, 5.614 mmol). Heat the reaction overnight at 70° C.Cool the mixture to ambient temperature, dilute with EtOAc, and filterover Celite®. Wash the organic fraction with water, dry over Na₂SO₄,filter and concentrate in vacuo. Purify by chromatography on silica geleluting with hexane/EtOAc (1:0, 4:1 and 1:1) to give the title compoundas an oil (0.295 g, 37%). GC-MS m/z: 284 (M⁺).4-(Pyridin-4-yl)-benzylamine: DissolveN-(tert-butoxycarbonyl)-4-(4-pyridyl)-benzylamine (363 mg, 1.276 mmol)in anhydrous DCM (10 mL). Add 4N hydrogen chloride in dioxane (10 mL)and stir overnight at ambient temperature. Concentrate in vacuo toobtain the hydrochloride salt in pure form as a solid. Dissolve thesolid in saturated aqueous NaHCO₃ and extract three times with DCM andthree more times with EtOAc. Combine the organic extracts, dry overNa₂SO₄, filter and concentrate to obtain the title compound as a solid(166 mg, 71%). GC-MS m/z: 184 (M⁺).

Preparation 70 4-(Pyridin-2-yl)-benzylamine

4-(2-Pyridyl)-benzaldehyde oxime: Add hydroxylamine hydrochloride (0.379g, 5.458 mmol) and a solution of NaOH (0.327 g, 8.187 mmol) in water (2mL) to a solution of 4-(2-pyridyl)-benzaldehyde (0.5 g, 2.729 mmol) inethanol (10 mL). Heat the mixture at 80° C. for 2 h. Cool to ambienttemperature and remove the solvent in vacuo. Partition the residuebetween EtOAc and water. Separate and dry the organic phase over Na₂SO₄,filter and concentrate in vacuo. Purify by chromatography on silica geleluting with hexane/EtOAc (1:0 and 4:1) to obtain the desiredintermediate (311 mg, 58%). GC-MS m/z: 198 (M⁺).4-(Pyridin-2-yl)-benzylamine: Add Pd/C (10%, 50 mg) and concentrated HCl(2 mL) to a solution of 4-(2-pyridyl)-benzaldehyde oxime (0.29 g, 1.46mmol) in absolute ethanol (20 mL). Hydrogenate the mixture at 50 psi for2 h. Filter over Celite®, wash with ethanol and concentrate in vacuo toobtain the hydrochloride salt in pure form as a solid. Dissolve thesolid in saturated aqueous NaHCO₃, extract the aqueous solution threetimes with DCM and three more times with EtOAc. Combine the organicextracts, dry over Na₂SO₄, filter and concentrate in vacuo to obtain thetitle compound as a solid (130 mg, 48%). GC-MS m/z: 184 (M⁺).

Preparation 71 4-(1-Methyl-1H-imidazol-2-yl)-benzylamine

[4-(1-Methyl-1H-imidazol-2-yl)-benzyl]-carbamic acid tert-butyl ester:Add 4-(N-tert-Butoxycarbonyl-aminomethyl)phenylboronic acid (1.9 g, 7.4mmol), 2-bromo-1-methyl-1H-imidazole (800 mg, 5.0 mmol),tetrakis(triphenylphosphine)-palladium(0) (287 mg, 0.25 mmol) andpotassium carbonate (860 mg, 6.2 mmol) to a flask containing toluene (10mL). Heat the mixture in a sealed flask at 90° C. for 16 h. Cool themixture, dilute with EtOAc (50 mL), filter through Celite®, andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc/methanol (49:50:1) to obtain the desired intermediate(1.2 g, 83%). GC-MS m/z: 287 (M⁺).4-(1-Methyl-1H-imidazol-2-yl)-benzylamine: Dissolve[4-(1-methyl-1H-imidazol-2-yl)-benzyl]-carbamic acid tert-butyl ester(500 mg, 1.7 mmol) in DCM (20 mL) and trifluoroacetic acid (5 mL). Stirthe mixture for 1 h at ambient temperature. Concentrate in vacuo andpurify by SCX chromatography to obtain the title compound (240 mg, 74%).MS (ES+) m/z: 188 (M+H)⁺.

Preparation 72 4-Ethanesulfonyl-benzylamine

4-Ethylthio-benzonitrile: Combine 4-mercapto-benzonitrile (0.4 g, 2.96mmol), bromoethane (1.4 mL, 8.88 mmol) and potassium carbonate (3.3 g,23.7 mmol) in anhydrous DMF (7 mL) and heat at 60° C. for 17 h. Cool thereaction mixture to ambient temperature and partition between brine (20mL) and EtOAc (20 mL). Separate the organic layer, dry over anhydrousNa₂SO₄ and concentrate. Purify by chromatography on silica gel elutingwith hexane/EtOAc (1:0, 9:1 and 4:1) to obtain the desired intermediateas a colorless oil (0.4 g, 83%).4-Ethanesulfonyl-benzonitrile: Dissolve 4-ethylthio-benzonitrile (0.4 g,2.4 mmol) in TFA (10 mL) and add slowly hydrogen peroxide (30 w %, 10mL) at 5° C. Stir the reaction mixture at ambient temperature for 2 hand partition between brine (20 mL) and DCM (20 mL). Separate theorganic layer, dry over anhydrous Na₂SO₄ and concentrate to obtain thedesired intermediate as a white solid (0.5 g, 100%). GC-MS m/z: 195(M⁺).4-Ethanesulfonyl-benzylamine: Combine 4-ethanesulfonyl-benzonitrile (0.7g, 3.5 mmol), Raney® 3201 nickel (slurry in water, 0.1 g), 2N ammonia inmethanol (20 mL) and hydrogenate at 50 psi for 17 h. Filter the reactionmixture through a pad of Celite® and concentrate in vacuo. Purify by SCXchromatography to obtain the title compound as a yellow oil (0.3 g,43%).

Preparation 73 4-(2-Propanesulfonyl)-benzylamine

Use a method similar to Preparation 72, using 4-mercapto-benzonitrile(0.5 g, 3.7 mmol) and 2-bromopropane (1.4 g, 11.38 mmol), to obtain thetitle compound as a yellow oil (0.3 g, 39% overall).

Preparation 74 4-Aminomethyl-N-tert-butyl-benzamide

N-tert-butyl-4-cyano-benzamide: Combine 4-cyanobenzoic acid (30 mg, 2.07mmol), tert-butylamine (0.5 mL, 4.13 mmol), triethylamine (0.4 mL, 2.89mmol), and HATU (1.1 g, 2.89 mmol) in anhydrous DME (7 mL). Stir atambient temperature for 17 h. Partition the reaction mixture betweenbrine (15 mL) and diethyl ether (15 mL), separate the organic layer, dryover anhydrous Na₂SO₄ and concentrate in vacuo. Purify by chromatographyon silica gel eluting with DCM to obtain the desired intermediate as awhite solid (0.4 g, 89%). MS (ES+) m/z: 203 (M+H)⁺.4-Aminomethyl-N-tert-butyl-benzamide: CombineN-tert-butyl-4-cyano-benzamide (0.4 g, 1.78 mmol), Raney® 3201 nickel(slurry in water, 0.03 g), 2N ammonia in methanol (20 mL) andhydrogenate at 50 psi for 1 h. Filter the reaction mixture through a padof Celite®, remove the solvent and purify by SCX chromatography toobtain the title compound as a colorless oil (0.4 g, 95%). MS (ES+) m/z:207 (M+H)⁺.

Preparation; 75 4-Aminomethyl-2-fluoro-N-tert-butyl-benzamide

4-Bromo-N-tert-butyl-2-fluoro-benzamide: Combine4-bromo-2-fluoro-benzoic acid (5.0 g, 22.83 mmol), thionyl chloride (10mL, 0.137 mmol) in toluene (10 mL) and reflux for 2 h. Evaporate thereaction mixture to obtain 4-bromo-2-fluoro-benzoyl chloride (5.0 g,93%) and use for the next step without further purification. Dissolvetert-butylamine (0.8 mL, 5.12 mmol) and triethylamine (0.8 mL, 6.32mmol) in anhydrous DCM (20 mL), cool to 0° C. and add a solution of4-bromo-2-fluoro-benzoyl chloride (1.0 g, 4.22 mmol) in anhydrous DCM(10 mL). Stir the reaction mixture at 0° C. for 10 min, warm to ambienttemperature and continue to stir for 30 min. Wash the reaction mixturewith brine (2×10 mL), dry the organic extracts over anhydrous Na₂SO₄,evaporate the solvent and purify by chromatography on silica gel elutingwith DCM to obtain the desired intermediate as a white solid (1.0 g,87%). MS (ES+) m/z: 275 (M+H)⁺.N-tert-Butyl-4-cyano-2-fluoro-benzamide: Combine4-bromo-N-tert-butyl-2-fluoro-benzamide (1.0 g, 3.65 mmol) and copper(I)cyanide (0.7 g, 7.29 mmol) in anhydrous DMF (10 mL) and reflux for 17 h.Cool the reaction mixture to ambient temperature and treat with 50%(v/v) aqueous ethylenediamine (20 mL). Extract the reaction mixture withdiethyl ether (3×10 mL), combine the organic extracts, wash with brine(2×10 mL) and dry the organic layer over Na₂SO₄. Evaporate the solventand purify by chromatography on silica gel eluting with hexane/EtOAc(1:0, 9:1, 4:1, 7:3 and 3:2) to obtain the desired intermediate as awhite solid (0.6 g, 77%). MS (ES+) m/z: 221 (M+H)⁺.4-Aminomethyl-2-fluoro-N-tert-butyl-benzamide: CombineN-tert-butyl-4-cyano-2-fluoro-benzamide (0.6 g, 1.78 mmol), Raney® 3201nickel (slurry in water, 30 mg), 2N ammonia in methanol (30 mL) andhydrogenate at 50 psi for 1 h. Filter the reaction mixture through a padof Celite®, concentrate in vacuo and purify by SCX chromatography toobtain the title compound as a colorless oil (0.6 g, 96%).

Preparation 76 4-Aminomethyl-2-fluoro-N-methyl-N′-propyl-benzamide

Use a method similar to Preparation 75, using 4-bromo-2-fluoro-benzoicacid (1.0 g, 4.56 mmol) and N-methyl-propylamine (0.5 mL, 5.05 mmol), togive the title compound as a colorless oil (0.5 g, 49%). GC-MS m/z: 224(M⁺).

Preparation 77 4-Aminomethyl-N-(2,2,2-trifluoro-ethyl)-benzamide

Use the General Procedure 6-1, using 2,2,2-trifluoroethylamine (197 mg,2 mmol) and 4-(tert-butoxycabonylamino-methyl)-benzoic acid, to give thetitle compound as a clear oil (440 mg, 94%). MS (ES+) m/z: 233 (M+H)⁺.

The compounds of Preparations 78-93 may be prepared essentially asdescribed in Preparation 77 by using4-tert-butoxycabonylamino-methyl)-benzoic acid and the appropriateamine. Overall yields and MS (ES) data are shown in the Table below.

Yield MS (ES) Preparation NH—R Compound (%) m/z 78

4-Aminomethyl-N-(2,2,3,3,3-pentafluoro-propyl)-benzamide 100 283(M + H)⁺79

(±)-4-Aminomethyl-N-(2,2,2-trifluoro-1-methyl-ethyl)-benzamide  78247(M + H)⁺ 80

4-Aminomethyl-N-(3,3,3-trifluoro-propyl)-benzamide 100 247(M + H)⁺ 81

(±)-4-Aminomethyl-N-(3,3,3-trifluoro-1-methyl-propyl)-benzamide 100261(M + H)⁺ 82

4-Aminomethyl-N-(cyclopentyl)-benzamide 100 219(M + H)⁺ 83

4-Aminomethyl-N-(cyclohexyl)-benzamide 100 233(M + H)⁺ 84

4-Aminomethyl-N-(cycloheptyl)-benzamide  80 247(M + H)⁺ 85

4-Aminomethyl-N-(tetrahydro-pyran-4-yl)-benzamide  56 ND 86

4-Aminomethyl-N-(4-methyl-phenyl)-benzamide 100 239(M − H)⁻ 87

4-Aminomethyl-N-(4-chloro-phenyl)-benzamide  84 259(M − H)⁻ 88

4-Aminomethyl-N-benzyl-benzamide  59 241 (M + H)⁺ 89

4-Aminomethyl-N-(3,4-difluoro-phenyl)-benzamide 100 ND 90

(R)-4-Aminomethyl-N-(1-phenyl-ethyl)-benzamide  94 255(M + H)⁺ 91

(S)-4-Aminomethyl-N-(1-phenyl-ethyl)-benzamide  94 255(M + H)⁺ 92

4-Aminomethyl-N-(1-methyl-1-phenyl-ethyl)-benzamide  22 269(M + H)⁺ 93

(±)-4-Aminomethyl-N-(1-methyl-2-phenyl-ethyl)-benzamide  85 269(M + H)⁺ND = Not determined

Preparation 94 4-(Piperidin-1-ylcarbonyl)-benzylamine

Use the General Procedure 6-1, using piperidine (373 mg, 4.4 mmol) and4-(tert-butoxycabonylamino-methyl)-benzoic acid to give the titlecompound as a white solid (1.03 g, 100%). MS (ES+) m/z: 219 (M+H)⁺.

Preparation 95 4-Aminomethyl-N-cyclohexyl-2-fluoro-benzamide

4-Bromo-N-cyclohexyl-2-fluoro-benzamide: Dissolve4-bromo-2-fluoro-benzoyl chloride (1 g, 4.21 mmol) in DCM and cool thesolution in an ice bath. Add triethylamine (0.87 mL, 6.32 mmol) andcyclohexylamine (502 mg, 5.1 mmol) and stir the mixture at ambienttemperature for 2 h. Partition the reaction mixture between brine andDCM. Dry the organic layer over Na₂SO₄, filter and concentrate in vacuoto give the desired intermediate as a white solid (1.24 g, 98%).4-Cyano-N-cyclohexyl-2-fluoro-benzamide: Heat a mixture of4-bromo-N-cyclohexyl-2-fluoro-benzamide (1.24 g, 4.13 mmol) and coppercyanide (740 mg, 8.26 mmol) in DMF (20 mL) to reflux for 16 h. Cool themixture to ambient temperature, add aqueous ethylenediamine and stir for30 min. Extract the mixture with hexane/EtOAc (1:1), dry the organiclayer over Na₂SO₄, filter and concentrate in vacuo. Purify the residueby chromatography on silica gel eluting with hexane/EtOAc (5:1) to givethe desired intermediate as a white solid (620 mg, 61%). MS (ES−) m/z:245 (M−H)⁻.4-Aminomethyl-N-cyclohexyl-2-fluoro-benzamide: Dissolve4-cyano-N-cyclohexyl-2-fluoro-benzamide (620 mg, 2.5 mmol) in 7N ammoniain methanol (150 mL) and hydrogenate at 500 psi pressure in the presenceof Raney® nickel (500 mg) for 16 h at 60° C. Filter the mixture andconcentrate in vacuo. Purify by SCX chromatography to give the titlecompound as a white solid (600 mg, 94%). MS (ES−) m/z: 251 (M−H)⁻.

Preparation 96 5-(Aminomethyl)-pyridine-2-carboxylic acidcyclohexylamide

Lithium 5-(tert-butoxycarbonylamino-methyl)-pyridine-2-carboxylate:Dissolve 5-aminomethyl-2-chloro-pyridine (2 g, 14 mmol) anddi-tert-butyl-dicarbonate (3.37 g, 15.4 mmol) in DCM (30 mL) and stir atroom temperature for 2 h. Concentrate the reaction mixture and purify bychromatography on silica gel eluting with hexane/EtOAc (10:1 and 5:1) togive 5-(tert-butoxycarbonylamino-methyl)-2-chloro-pyridine as a yellowsolid (3.6 g, 100%). MS (ES+) m/z: 243 (M+H)⁺. Dissolve5-tert-butoxycarbonylamino-methyl)-2-chloro-pyridine (1 g, 4.12 mmol) ina mixture of ethanol (15 mL) and DMF (5 mL), and add potassium carbonate(427 mg, 3.09 mmol), palladium(II) acetate (92 mg, 0.4 mmol) anddiphenylphosphinoferrocene (240 mg, 0.44 mmol). Pressurize the mixture25 to 15 psi with carbon monoxide gas and heat the reaction mixture to90° C. for 16 h. Filter the reaction mixture, concentrate the filtrate,and partition the residue between water and hexane/EtOAc (1:1). Dry theorganic layer over Na₂SO₄, filter, and concentrate in vacuo. Purify theresidue by chromatography on silica gel eluting with hexane/EtOAc (3:2)to give 5-(tert-butoxycarbonylamino-methyl)-pyridine-2-carboxylic acidethyl ester as a brown oil (920 mg, 80%). MS (ES+) m/z: 281 (M+H)⁺.Dissolve 5-(tert-butoxycarbonylamino-methyl)pyridine-2-carboxylic acidethyl ester (920 mg, 3.28 mmol) in a mixture of water/THF (1:2, 15 mL)and add lithium hydroxide (87 mg, 3.61 mmol). Stir the mixture atambient temperature for 4 h and concentrate to a solid. Dry the materialby azeotrope distillation with toluene to give the desired intermediateas a brown solid (1 g, 100%). MS (ES+) m/z: 253 (M+H)⁺.5-(Aminomethyl)-pyridine-2-carboxylic acid cyclohexylamide: Use theGeneral Procedure 6-2, using cyclohexylamine (1 mL), lithium5-(tert-butoxycarbonylamino-methyl)-pyridine-2-carboxylate (1 g, 3.96mmol) and DIEA (5 mL) as cosolvent, to give the title compound as awhite solid (200 mg, 22%). MS (ES+) m/z: 234 (M+H)⁺.

Preparation 97 5-(Aminomethyl)-pyridine-2-carboxylic acid4-fluoro-benzylamide

Use the General Procedure 6-2, using 4-fluoro-benzylamine (551 mg, 4.4mmol), lithium5-(tert-butoxycarbonylamino-methyl)-pyridine-2-carboxylate (740 mg, 2.93mmol) and DIEA (2.6 mL) as cosolvent, to give the title compound as awhite solid (200 mg, 26%). MS (ES+) m/z: 260 (M+H)⁺.

Preparation 98 2-Aminomethyl-5-(2,2,2-trifluoroethoxy)-pyridine

2-Methyl-5-(2,2,2-trifluoroethoxy)-pyridine: Add5-hydroxy-2-methyl-pyridine (3.3 g, 30.6 mmol), potassium carbonate (17g, 122.4 mmol) and 2-bromo-1,1,1-trifluoroethane (10 g, 61.2 mmol) to aflask containing DMF (60 mL) and heat to 95° C. for 20 h. Cool themixture, dilute with aqueous 10% NaCl (20 mL) and extract withhexane/EtOAc (1:1, 100 mL). Filter the bi-phasic mixture throughCelite®, separate and wash the organic layer with aqueous 10% NaCl (3×50mL) and concentrate in vacuo. Purify by chromatography on silica geleluting with hexane/EtOAc (9:1 to 1:1) to obtain the desiredintermediate (4.1 g, 70%).2-Bromomethyl-5-(2,2,2-trifluoroethoxy)-pyridine: Add2-methyl-5-(2,2,2-trifluoroethoxy)-pyridine (2.5 g, 13.1 mmol), NBS (2.3g, 13.1 mmol) and benzoyl peroxide (50 mg) to a flask containing carbontetrachloride (30 mL). Heat the mixture at 80° C. in a sealed flask for16 h. Cool the flask, add NBS (1.1 g, 6.5 mmol) and benzoyl peroxide(100 mg), then continue heating at 80° C. for an additional 5 h. Coolthe mixture, dilute with DCM, then wash with saturated sodium bisulfite(10 mL). Collect the organic layer and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (9:1) to obtainthe desired intermediate (460 mg, 13%).2-Aminomethyl-5-(2,2,2-trifluoroethoxy)-pyridine: Dissolve sodium azide(270 mg, 4.0 mmol) in DM (30 mL). Cool the solution to 0° C., then add2-bromomethyl-5-(2,2,2-trifluoroethoxy)-pyridine (440 mg, 1.6 mmol) at0° C. Slowly heat the mixture from 0° C. to 80° C. over 30 min. Cool thereaction, dilute with EtOAc (100 mL) and wash with 10% aqueous NaCl(3×25 mL). Collect the organic layer and concentrate in vacuo to avolume of 50 mL. Transfer the solution to a pressure vessel. Add 10%Pd/C (Degussa type E101, 50% water by wt, 500 mg) and pressurize thevessel under hydrogen (10 psi) for 1 h with stirring. Filter the mixturethrough Celite® and wash filter cake with warm methanol followed by DCM.Concentrate in vacuo, then purify by chromatography on silica geleluting with DCM/2M ammonia in methanol (20:1) to obtain the titlecompound (180 mg, 54%). MS (ES+) m/z: 207 (M+H)⁺.

Preparation 992-Aminomethyl-5-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-pyridine

5-Chloro-pyridine-2-carbonitrile: Add 2,5-dichloropyridine (6.0 g, 40.5mmol), zinc cyanide (2.9 g, 24.7 mmol), zinc dust (16 mg, 1.8 mmol) and1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.98mmol) to a flask containing DMF (40 mL). Heat the mixture to reflux for5 h, then cool to ambient temperature. Dilute the mixture with EtOAc(300 mL) and wash with 10% aqueous NaCl (3×75 mL). Collect the organiclayer, concentrate in vacuo and purify by chromatography on silica geleluting with hexane/EtOAc (9:1 to 1:1) to obtain the desiredintermediate (2.6 g, 46%).5-Fluoro-pyridine-2-carbonitrile: Add 5-chloro-pyridine-2-carbonitrile(3.0 g, 21.7 mmol) and potassium fluoride (3.9 g, 67.1 mmol) to a flaskcontaining NMP (75 mL). Heat the mixture to reflux for 16 h. Addadditional potassium fluoride (1.0 g, 17.2 mmol) and NMP (10 mL), thencontinue heating at reflux for 3 h. Cool the mixture, dilute with EtOAc,then wash with saturated NaCl (3×50 mL). Collect the organic layer,concentrate in vacuo and purify by chromatography on silica gel elutingwith hexane/EtOAc (20:1) to obtain the desired intermediate (1.5 g,53%).5-(2,2,2-Trifluoro-1,1-dimethyl-ethoxy)-pyridine-2-carbonitrile: Add2-trifluoromethyl-2-propanol (1.1 g, 8.3 mmol) slowly to a slurry ofsodium hydride (202 mg, 60% mineral oil, washed with hexane) in HMPA (3mL) under nitrogen. Stir the slurry for 15 min, then add5-fluoro-pyridine-2-carbonitrile (510 mg, 4.2 mmol). Stir the slurry for16 h at ambient temperature. Adjust the mixture to pH 9 with sodiumcarbonate then extract with diethyl ether (3×50 mL). Collect the organiclayer, dry over Na₂SO₄ and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (95/5 to 80/20)to obtain the desired intermediate (768 mg, 79%). GC-MS m/z: 230 (Me).2-Aminomethyl-5-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-pyridine: Add5-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-pyridine-2-carbonitrile (580 mg,2.5 mmol), 10% Pd/C (Degussa type E101, 50% water by wt, 400 mg) andtrifluoroacetic acid (2 mL) in ethanol (20 mL) to a pressure vessel.Pressurize the vessel to 50 psi with hydrogen for 1 h. Filter themixture through Celite® and wash the cake with warm ethanol followed byDCM under a nitrogen atmosphere. Concentrate in vacuo to obtain thecrude product as the trifluoroacetic acid salt. Prepare the free basewith SCX chromatography, then purify using silica gel chromatographyeluting with DCM/2M ammonia in methanol (20:1) to obtain the titlecompound (261 mg, 45%). MS (ES+) m/z: 235 (M+H)⁺.

Preparation 100(±)-2-Aminomethyl-5-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine

(±)-5-(2,2,2-Trifluoro-1-methyl-ethoxy)-pyridine-2-carbonitrile: Add1,1,1-trifluoro-2-propanol (971 mg, 8.5 mmol) slowly to a slurry ofsodium hydride (205 mg, 60% mineral oil, washed with hexane) in HMPA (8mL) under nitrogen at 0° C. Allow the slurry to warm to ambienttemperature and stir for 5 min. Add 5-chloro-pyridine-2-carbonitrile(590 mg, 4.2 mmol), then heat the mixture at 90° C. for 4 h. Adjust themixture to pH 9 with sodium carbonate then extract with diethyl ether(2×50 mL). Dry the combined organic extracts over Na₂SO₄ and concentratein vacuo. Purify by chromatography on silica gel eluting withhexane/EtOAc (95/5 to 80/20) to obtain the desired intermediate (818 mg,89%). GC-MS m/z: 216 (M⁺).(±)-2-Aminomethyl-5-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine: Add(±)-5-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carbonitrile (810 mg,3.7 mmol), 10% Pd/C (Degussa type E101, 50% water by wt, 300 mg), andtrifluoroacetic acid (4 mL) in methanol (50 mL) to a pressure vessel.Pressurize the vessel to 40 psi with hydrogen for 0.25 h. Filter themixture through Celite® and wash the cake with warm ethanol followed byDCM under a nitrogen atmosphere. Concentrate in vacuo to obtain thecrude product as a trifluoroacetic acid salt. Prepare the free base withSCX ion chromatography, then purify by chromatography on silica geleluting with DCM/2M ammonia in methanol (20:1) to obtain the titlecompound (676 mg, 82%). GC-MS m/z: 220 (M⁺).

Preparation 101 2-Aminomethyl-5-fluoro-pyridine

2-Bromo-5-fluoro-pyridine: Cool 48% hydrobromic acid (44 mL, 4.4 equiv.)in an ice/acetone bath to −5° C., then add 2-amino-5-fluoropyridine(10.0 g, 89.2 mmol, 1.0 equiv.) portion wise over 10 min and maintainthe temperature below 5° C. throughout addition. Add bromine (14 mL, 3,equiv.) at 0° C. over 2 h and maintain the temperature at 0° C.throughout the addition. Stir the mixture for 30 min, then add asolution of sodium nitrite (15.4 g) in water (30 mL) via addition funnelover 2 h and maintain the temperature below 0° C. throughout theaddition. Stir the mixture for 30 min., then add a solution of NaOH (34g) in water (34 mL) over 1 h and maintain the temperature below 10° C.Stir the mixture for 3 min. Extract with diethyl ether (5×250 mL), drythe combined organic extracts over Na₂SO₄ and concentrate in vacuo togive the desired intermediate (12.1 g, 77%).(5-Fluoro-pyridin-2-yl)-methanol: At −78° C. under nitrogen, addn-butyllithium (2.5 M in hexane, 16.4 mL, 40.9 mmol) via syringe to asolution of 2-bromo-5-fluoro-pyridine (6.0 g, 34.1 mmol) in toluene (220mL), while keeping the reaction temperature below −60° C. Stir themixture at −78° C. and then add DMF (3.4 mL, 44.3 mmol) and stir for 1 hat this temperature. Warm to −10° C. and quench with methanol (10 mL).Concentrate the mixture to half of the volume in vacuo. Dilute withmethanol (150 mL), cool the mixture to −78° C. and add sodiumborohydride (3.2 g, 85.2 mmol) portion wise over 5 min. Warm the mixtureto ambient temperature and stir for 2 h. Quench with water (10 mL) andremove the organic solvent in vacuo to obtain an oil/water mixture.Extract with diethyl ether (3×100 mL), dry the combined organicextracts, wash with brine, dry and concentrate in vacuo to obtain thedesired intermediate as an oil (3.9 g, 91%).Methanesulfonic acid (5-fluoro-pyridin-2-yl)methyl ester: Addmethanesulfonyl chloride (1.8 mL, 23.5 mmol) to a solution of(5-fluoro-pyridin-2-yl)-methanol (2.5 g, 19.7 mmol) and triethylamine(8.2 mL, 59.0 mmol) in DCM (150 mL) at 0° C. under nitrogen. Stir themixture for 30 min and concentrate in vacuo. Dilute with water (20 mL)and extract the mixture with EtOAc (3×50 mL). Combine the organicextracts and concentrate in vacuo. Purify by chromatography on silicagel eluting with hexane/EtOAc to obtain the desired intermediate (2.2 g,54%).2-Aminomethyl-5-fluoro-pyridine: Dissolve methanesulfonic acid(5-fluoro-pyridin-2-yl)-methyl ester (1.5 g, 7.3 mmol) in DMF (5 mL) andadd sodium azide (950 mg, 14.6 mmol). Stir the mixture for 30 min, thendilute with hexane/EtOAc (1:1, 50 mL). Wash the mixture with 10% aqueousNaCl (3×10 mL). Dry the combined organic extracts over Na₂SO₄ and removehalf of the solvent in vacuo. Add EtOAc (20 mL) and a suspension of 10%Pd/C (200 mg) in EtOAc (2 mL). Stir the mixture for 1 h at ambienttemperature in a pressurized vessel under 50 psi of hydrogen. Filter theslurry through Celite® and concentrate in vacuo to obtain2-aminomethyl-5-fluoro-pyridine (613 mg, 60% yield, 80% purity byGC/MS). GC-MS m/z: 126 (M⁺).

Preparation 102 3-Aminomethyl-5-fluoro-pyridine

In a Parr Bottle add 2,6-dichloro-3-cyano-5-fluoropyridine (20 g, 0.105mol), ethanol (336 mL), triethylamine (24 mL), and 5% Pd/C (4 g). Placeon a Parr Shaker Apparatus under 60 psi hydrogen for 1 h at ambienttemperature. Filter the reaction mixture and bubble ammonia gas intofiltrate for 10 min. Add Raney® nickel (5.2 g) and place on a ParrShaker Apparatus under 500 psi hydrogen for 18 h at 60-70° C. Filter thereaction mixture and concentrate in vacuo. Dissolve in methanol and add1N hydrogen chloride in ether until form a precipitate. Cool in an icebath, filter off the precipitate, wash the solid several times withether, and dry to give the title compound as the hydrochloride salt (12g, 70%). MS (ES+) m/z: 127 (M+H)⁺. Dissolve the hydrochloride salt inwater, add 0.1 N aqueous NaOH to adjust to pH 10, extract with DCM, drythe organic layer over Na₂SO₄, filter and concentrate to give the titlecompound.

Preparation 103 3-Aminomethyl-4-trifluoromethyl-pyridine

Add 4-trifluoromethyl-nicotinonitrile (1.0 g, 5.8 mmol) and ethanol wetRaney® activated nickel (0.2 g) to a Parr pressure vessel. Immediatelyadd, at ambient temperature, 2B-ethanol (25 mL) previously saturatedwith ammonia gas and seal the vessel. Purge the reaction vessel withnitrogen, pressurize the reaction mixture with hydrogen (400 KPa), sealthe vessel, agitate the reaction and heat to 40° C. Continue thereaction for 20 h then turn off the heat and allow the reaction mixtureto cool to ambient temperature. Vent the excess hydrogen from the vesseland purge the vessel with nitrogen. Filter the reaction mixture toremove the Raney® nickel, wash with ethanol and concentrate in vacuo.Purify by SCX chromatography to give the title compound (560 mg, 55%).MS (ES+) m/z: 177 (M+H)⁺.

Preparation 104 2-Aminomethyl-6-fluoropyridine Dihydrochloride

3-Fluoropyridine-N-Oxide: Dissolve 3-fluoropyridine (2.5 g, 25.749 mmol)in anhydrous DCM (75 mL). Add m-CPBA (70% suspension, 12.696 g, 51.499mmol) and stir at ambient temperature overnight. Wash the reactionmixture with saturated aqueous NaHCO₃, dry the organic phase overNa₂SO₄, filter, and concentrate in vacuo. Purify by chromatography onsilica gel eluting with DCM and DCM/methanol (97:3) to obtain thedesired intermediate as a solid (1.413 g, 49%). MS (ES+) m/z: 115(M+H)⁺.2-Cyano-3-fluoropyridine: Dissolve 3-fluoropyridine-N-oxide (1.0 g,8.687 mmol) in anhydrous acetonitrile (100 mL). Add triethylamine (1.319g, 1.82 mL, 13.031 mmol), trimethylsilylcyanide (3.447 g, 4.63 mL,34.749 mmol) and heat the mixture to reflux overnight. Cool to ambienttemperature and concentrate in vacuo. Dissolve the residue in EtOAc andwash with saturated aqueous NaHCO₃. Dry the organic layer over Na₂SO₄,filter, and concentrate in vacuo. Purify by chromatography on silica geleluting with hexane/EtOAc (1:0 and 17:3) to give the desiredintermediate as a solid (746 mg, 70%). GC-MS m/z: 122 (M⁺).2-Aminomethyl-3-fluoropyridine dihydrochloride: Dissolve2-cyano-3-fluoropyridine (300 mg, 2.457 mmol) in absolute ethanol (12mL). Add 10% Pd/C (93 mg) and concentrated HCl (0.614 mL, 7.37 mmol).Hydrogenate at 40 psi overnight. Filter through Celite® and concentratein vacuo to give the title compound as a solid (440 mg, 90%). MS (ES+)m/z: 127 (M+H)⁺.

Preparation 105 2-Aminomethyl-6-fluoropyridine Dihydrochloride

2-Cyano-6-fluoropyridine: Dissolve 2,6-difluoropyridine (12 g, 104.2mmol) in anhydrous DMSO (5 mL). Add a solution of sodium cyanide (1.3 g,26.53 mmol) in DMSO (60 mL) over 12 h using a syringe pump. Heat themixture to 100° C. overnight. Cool to ambient temperature, dilute withEtOAc (500 mL), and wash with brine. Dry the organic phase over Na₂SO₄,filter, and concentrate in vacuo. Purify by chromatography on silica geleluting with hexane/EtOAc (1:0 and 4:1) to give the desired intermediateas a solid (723 mg, 22%). GC-MS m/z: 122 (M⁺).2-Aminomethyl-6-fluoropyridine Dihydrochloride: Dissolve2-cyano-6-fluoropyridine (300 mg, 2.46 mmol) in absolute ethanol (12mL). Add 10% Pd/C (93 mg) and concentrated HCl (0.614 mL, 7.37 mmol).Hydrogenate at 40 psi overnight. Filter through Celite® and concentrateto give the title compound as a solid (356 mg, 73%). MS (ES+) m/z: 127(M+H)⁺.

Preparation 106 4-Aminomethyl-N-(pyridin-2-yl-methyl)-benzamide

Use the General Procedure 6-2, using 2-(aminomethyl)pyridine (181 mg,0.172 mL, 1.67 mmol) and 4-(tert-butoxycarbonylamino-methyl)-benzoicacid (420 mg, 1.67 mmol) to give the title compound as a solid (427 mg,100%). MS (ES+) m/z: 242 (M+H)⁺.

The compounds of Preparations 107-1.17 may be prepared essentially asdescribed in Preparation 106 by using4-(tert-butoxycarbonylamino-methyl)-benzoic acid and the appropriateamine. Overall yields and MS (ES+) data are shown in the Table below.

MS (ES+) Yield or Prep. NHR Compound (%) GC-MS 107

4-Aminomethyl-N-(thiophen-2-yl-methyl)-benzamide 100 247(M + H)⁺ 108

4-Aminomethyl-N-(3-fluoro-pyridin-2-ylmethyl)-benzamide  58 259(M)⁺ 109

4-Aminomethyl-N-(6-fluoro-pyridin-2-ylmethyl)-benzamide  98 259(M)⁺ 110

4-Aminomethyl-N-(5-fluoro-pyridin-2-ylmethyl)-benzamide  67 259(M)⁺ 111

4-Aminomethyl-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-benzamide  62310(M + H)⁺ 112

4-Aminomethyl-N-(4-trifluoromethyl-pyridin-2-ylmethyl)-benzamide  76309(M)⁺ 113

4-Aminomethyl-N-(5-trifluoromethyl-pyridin-2-ylmethyl)-benzamide  65310(M + H)⁺ 114

4-Aminomethyl-N-(2-thiophen-2-yl-ethyl)-benzamide 100 261(M + H)⁺ 115

4-Aminomethyl-N-(2-pyridin-2-yl-ethyl)-benzamide  81 256(M + H)⁺ 116

4-Aminomethyl-N-(2-pyridin-3-yl-ethyl)-benzamide  97 256(M + H)⁺ 117

4-Aminomethyl-N-(2-pyridin-4-yl-ethyl)-benzamide  96 256(M + H)⁺

Preparation 118 (±)-1-(3-Fluorophenyl)ethylamine

Add sodium cyanoborohydride (452 mg, 7.2 mmol) to a solution of3-fluoroacetophenone (500 mg, 3.6 mmol) and ammonium acetate (2.8 g, 36mmol) in methanol (11 mL). Stir the mixture for 96 h at ambienttemperature under a nitrogen atmosphere. Adjust to pH 2 with 2M hydrogenchloride in diethyl ether. Concentrate the slurry in vacuo, dilute theresidue with DCM and wash with 5N aqueous NaOH followed by saturatedaqueous NaHCO₃. Dry the organic layer, concentrate in vacuo to half ofthe volume, and load the solution onto a SCX column (pre-wash columnwith methanol followed by DCM, then elute with 2M ammonia in methanol).Concentrate the fractions to half of the volume to remove ammonia, addexcess of 2M hydrogen chloride in diethyl ether and concentrate toobtain the hydrochloride salt (70:30 mixture of title compound anddimer). Purify by chromatography on silica gel eluting with DCM/2Mammonia in methanol (20:1) to obtain the title compound (323 mg, 51%).MS (ES+) m/z: 140 (M+H)⁺

Preparation 119 1-(3-Fluorophenyl)ethylamine, Isomer 2

Set-up flask equipped with condenser, mechanical stirrer and additionfunnel. Add 3-fluoroacetophenone (25 g, 0.18 mol) and formic acid (4.2g, 0.09 mol) via addition funnel to a flask containing formamide (32.6g, 0.72 mol) at 140° C. over 15 min, and then heat the mixture to 160°C. Add formic acid successively (4.2 g, 0.5 equiv.) via addition funnelto the flask every hour for 4 h while maintaining the reactiontemperature at 160° C. Cool the reaction mixture, extract with toluene(3×100 mL), and concentrate the organic layer in vacuo. Add aqueous HCl(37%, 40 mL) to the residue and heat to reflux for 2 h. Cool to ambienttemperature and wash the aqueous mixture with toluene (2×100 mL), thenbasify the aqueous mixture with 5N aqueous NaOH (120 mL). Extract thebasic mixture with EtOAc (3×100 mL), dry the combined organic extractsover Na₂SO₄ and filter. Acidify the filtrate with 2M hydrogen chloridein diethyl ether to pH 2 and concentrate in vacuo to a solid. Suspendthe solid in diethyl ether, filter and wash with diethyl ether. Dry thesolid in a vacuo-oven at 50° C. to obtain(±)-1-(3-fluorophenyl)ethylamine hydrochloride (21.5 g, 68%). MS (ES+)m/z: 140 (M+H)⁺.

Dissolve (±)-1-(3-fluorophenyl)ethylamine hydrochloride (42.5 g, 0.24mol) in THF (520 mL) and saturated aqueous NaHCO₃ (430 mL). Adddi-tert-butyl-dicarbonate (69 g, 0.31 mol) and stir for 16 h at ambienttemperature. Separate the organic layer, dilute with EtOAc (300 mL) andwash with 2N aqueous NaOH (1×400 mL) and water (2×200 mL). Concentratethe organic layer in vacuo. Purify by chromatography on silica geleluting with hexane/EtOAc (9:1) to obtain(±)-N-[1-(3-fluorophenyl)ethyl]-carbamic acid tert-butyl ester (56 g,97%). GC-MS m/z: 183 [(M-C₄H₉)⁺].

Separate the racemic mixture of (±)N-[1-(3-fluorophenyl)ethyl]-carbamicacid tert-butyl ester by normal phase chiral chromatography (ChiralcelOD 8×34 cm, elute with 95:5, heptane/isopropanol). Using the GeneralProcedure 1-4, deprotect the desired isomer [20.7 g, >95% ee (ChiralcelOD, 4.6×250 mm, eluent: 95:5 heptane/isopropanol with 0.2% DMEA, 1.0mL/min)] to obtain the title compound (9.4 g, 78%). MS (ES+) m/z: 140(M+H)⁺.

Preparation 120 (±)-1-(2-Fluorophenyl)ethylamine

Add sodium cyanoborohydride (1.8 g, 29 mmol) to a solution of2-fluoro-acetophenone (2.0 g, 14.5 mmol) and ammonium acetate (11.2 g,145 mmol) in methanol (45 mL). Stir the mixture for 20 h at ambienttemperature under a nitrogen atmosphere. Adjust the mixture to pH 1 with2M hydrogen chloride in diethyl ether. Concentrate the slurry in vacuo,dilute the residue with DCM and wash with 5N aqueous NaOH. Dry theorganic layer, concentrate carefully, as the amine is volatile, underreduced pressure to one third of the volume, and load the material ontoan SCX column (pre-wash column with methanol, followed by DCM, elutewith 2M ammonia in methanol). Concentrate the fraction to one half ofthe volume to remove the ammonia, then add excess 2M hydrogen chloridein diethyl ether and concentrate to obtain the hydrochloride salt.Purify by chromatography on silica gel eluting with DCM/2M ammonia inmethanol (20:1) to obtain the title compound (280 mg, 13%). MS (ES+)m/z: 140 (M+H)⁺.

Preparation 121 1-(2-Fluorophenyl)ethylamine, Isomer 1

Use a method similar to the General Procedure 6-3, using2-fluoroacetophenone (1.4 g, 9.9 mmol) and(R)-(+)-2-methyl-2-propanesulfinamide (1.0 g, 8.2 mmol). Purify bychromatography on silica gel eluting with hexane/EtOAc/2M ammonia inmethanol (90:9:1 to 50:45:5). Add 4M hydrogen chloride in dioxane toobtain the title compound as the hydrochloride (600 mg, 35%). MS (ES+)m/z: 140 (M+H)⁺. Dissolve the hydrochloride in an aqueous solution ofcesium carbonate (1.5 equiv.) and extract with toluene to obtain thefree base.

The compounds of Preparations 122-141 may be prepared essentially asdescribed in Preparation 121 by using(R)-(+)-2-methyl-2-propanesulfinamide or(S)-(−)-2-methyl-2-propanesulfinamide and the appropriate acetophenone.Overall yields and mass spectrum data are shown in the Table below.

MS (ES+) Yield or Prep. R Compound (%) GC-MS 122 3-CN1-(3-Cyanophenyl)ethylamine, 37 130 Isomer 1 (M + H—NH₃)⁺ 123 3-CN 1-(3-49 130 Cyanophenyl)ethylamine, (M + H—NH₃)⁺ Isomer 2 124 4-CN 1-(4- 49130 Cyanophenyl)ethylamine, (M + H—NH₃)⁺ Isomer 1 125 4-CN 1-(4- 49 130Cyanophenyl)ethylamine, (M + H—NH₃)⁺ Isomer 2 126 2-Cl 1-(2- 25 156Chlorophenyl)ethylamine, (M + H)⁺ Isomer 1 127 3-Cl 1-(3- 68 156Chlorophenyl)ethylamine, (M + H)⁺ Isomer 1 128 3-CF₃ 1-(3- 40 190Trifluoromethylphenyl)- (M + H)⁺ ethylamine, Isomer 1 129 4-CF₃ 1-(4- 70190 Trifluoromethylphenyl)- (M + H)⁺ ethylamine, Isomer 2 130 3-Cl,1-(3-Chloro-4- 66 174 4-F fluorophenyl)-ethylamine, (M + H)⁺ Isomer 1131 3-Cl- 1-(3-Chloro-4- 68 174 4-F fluorophenyl)-ethylamine, (M + H)⁺Isomer 2 132 2,3-diF 1-(2,3-Difluorophenyl)- 20 141 ethylamine, Isomer 1(M + H—NH₃)⁺ 133 2,3-diF 1-(2,3-Difluorophenyl)- 45 141 ethylamine,Isomer 2 (M + H—NH₃)⁺ 134 2,4-diF 1-(2,4-Difluorophenyl)- 58 158ethylamine, Isomer 1 (M + H)⁺ 135 2,4-diF 1-(2,4-Difluorophenyl)- 49 158ethylamine, Isomer 2 (M + H)⁺ 136 3,5-diF 1-(3,5-Difluorophenyl)- 26 158ethylamine, Isomer 1 (M + H)⁺ 137 3,5-diF 1-(3,5-Difluorophenyl)- 83 158ethylamine, Isomer 2 (M + H)⁺ 138 3,4-diF 1-(3,4-Difluorophenyl)- 67 158ethylamine, Isomer 1 (M + H)⁺ 139 3,4-diF 1-(3,4-Difluorophenyl)- 77 158ethylamine, Isomer 2 (M + H)⁺ 140 3,4,5- 1-(3,4,5-Trifluorophenyl)- 20176 triF ethylamine, Isomer 2 (M + H)⁺ 141 3,5- 1-(3,5-bis- 49 258 diCF₃trifluoromethylphenyl)- (M + H)⁺ ethylamine, Isomer 2 142 2-OCF₃ 1-(2-47 ND Trifluoromethoxyphenyl)- ethylamine, Isomer 2 143 2-Me1-(2-Methyl)-ethylamine, 13 136 Isomer I (M⁺) ND = Not determined

Preparation 144 (±)-1-(2,5-Difluorophenyl)ethylamine

Slurry 2′,5′-difluoroacetophenone (0.9 g, 5.76 mmol), ammonium acetate(4.44 g, 57.5 mmol) and sodium cyanoborohydride (755 mg, 12 mmol) inanhydrous methanol (25 mL) and stir for 18 h at ambient temperature.Acidify with 5N aqueous HCl (5 mL), dilute, extract with ethyl ether(3×150 mL), basify aqueous layer with 5N aqueous NaOH, extract with DCM(3×75 mL), wash the organic layer with brine, dry over MgSO₄, filter andconcentrate in vacuo. Purify by SCX chromatography to give a mixture of(±)-1-(2,5-difluorophenyl)ethylamine andbis-[1-(±)-2,5-difluorophenyl)ethyl]-amine (total 400 mg, crude weight).MS (ES+) m/z: 158 (M+H)⁺ and m/z: 298 (M+H)⁺.

Preparation 145 (±)-1-(3,5-Difluoro-4-methoxyphenyl)ethylamine

Slurry 3′,5′-difluoro-4′-methoxyacetophenone (1.0 g, 5.0 mmol), ammoniumacetate (4.14 g, 50 mmol) and sodium cyanoborohydride (630 mg, 20 mmol)in anhydrous methanol (35 mL) and stir for 18 h at ambient temperature.Acidify with 1N aqueous HCl (5 mL), dilute, extract with ethyl ether(3×150 mL), basify aqueous with 1N aqueous NaOH, extract with DCM (3×50mL), wash the organic extracts with brine, dry over MgSO₄, filter andconcentrate in vacuo. Purify by SCX chromatography to give crude thetitle compound as a yellow oil (380 mg).

Preparations 146 and 147 1-(4-Phenoxyphenyl)-ethylamine, Isomer 1 andIsomer 2

Mix 4-phenoxyacetophenone (5.3 g, 25 mmol), ammonium acetate (14.5 g,187.5 mmol) and sodium cyanoborohydride (3.2 g, 50 mmol) in anhydrousmethanol (200 mL). Stir for 18 h at ambient temperature. Acidify with 1Naqueous HCl (10 mL), dilute, extract with ethyl ether (3×150 mL), dryover MgSO₄, filter and concentrate in vacuo. Purify by chromatography onsilica gel eluting sequentially with hexane/EtOAc (4:1, 1:1 and 0:1) andEtOAc/methanol (1:1) to give (±)-1-(4-phenoxyphenyl)-ethylamine (1.6 g,30%). Dissolve the racemate (1.1 g, 5.2 mmol) in DCM (100 mL), addtriethylamine (1.6 mL, 11.4 mmol) followed by di-tert-butyl-dicarbonate(1.7 g, 7.8 mmol). Purify by chromatography on silica gel eluting withhexane/EtOAc (9:1) to give [α-methyl-(4′-phenoxy)-benzylamino]carbamicacid tert-butyl ester as an off-white solid (1.3 mg, 81%). Separate viachiral chromatography (heptane/isopropanol/DMEA 95:5:0.2, 4.6×250 mmChiralpak AD, 1 mL/min, UV detector at 260 nm) to give[α-methyl-(4′-phenoxy)benzylamino]carbamic acid tert-butyl ester, isomer1 (315 mg, chiral HPLC: t_(R)=7.35 min; 99.1% ee) and[α-methyl-(4′-phenoxy)benzyl-aminocarbamic acid tert-butyl ester, isomer2 (400 mg, chiral HPLC: t_(R)=8.7 min; 97.2% ee). Dissolve[α-methyl-(4′-phenoxy)benzylamino]carbamic acid tert-butyl ester isomer1 or isomer 2 in DCM/trifluoroacetic acid (1:1, 20 mL) to give, aftersolvent evaporation and chromatography over SCX column,1-(4-phenoxyphenyl)-ethylamine, isomer 1 (Preparation 146) and1-(4-phenoxyphenyl)-ethylamine, isomer 2 (Preparation 147). MS (ES+)m/z: 214 (M+H)⁺.

Preparation 148 (5-Fluoro-indan-1-yl)amine, Isomer 1

Use a method similar to the General Procedure 6-3 to react5-fluoro-indan-1-one (1.5 g, 9.9 mmol) and(R)-(+)-2-methyl-2-propanesulfinamide (1.0 g, 8.3 mmol). Purify bychromatography on silica gel eluting with hexane/EtOAc (5:2). Add 4Mhydrogen chloride in dioxane to obtain the title compound as thehydrochloride (254 mg, 16%). MS (ES+) m/z: 152 (M+H)⁺. Dissolve thehydrochloride in an aqueous solution of cesium carbonate (1.5 equiv.)and extract with toluene to obtain the free base.

Preparation 149 1-Phenyl-cyclopropylamine

Dissolve 1-phenyl-cyclopropanecarboxylic acid (2.5 g, 15.4 mmol) in amixture of sulfuric acid (12.5 mL) and DCM (25 mL). Add sodium azide(2.3 g, 35.4 mmol) by small portions at ambient temperature. Heat thereaction mixture at 50° C. for 8 h, cool to 0° C. and slowly add 2Maqueous NaOH until pH 11. Extract the reaction mixture with DCM (3×100mL), combine the organic extracts and dry over anhydrous Na₂SO₄.Evaporate the solvent and purify by chromatography on silica gel elutingwith DCM and DCM/2M ammonia in methanol (9:1) to obtain the titlecompound as a brown oil (1.1 g, 54%). MS (ES+) m/z: 134 (M+H)⁺.

Preparation 150 1-(2,4-Dichlorophenyl)-cyclopropylamine

Use a method similar to Preparation 149, using1-(2,4-dichlorophenyl)-cyclopropanecarboxylic acid (3.5 g, 15.4 mmol),to obtain the title compound as a yellow oil (1.0 g, 32%). MS (ES+) m/z:203 (M+H)⁺.

Preparation 151 4-Methylamino-benzo[1,3]dioxole

Benzo[1,3]dioxol-4-yl-methanol: Dissolvebenzo[1,3]dioxole-4-carbaldehyde (2.0 g, 13.3 mmol) in anhydrous THF (30mL) and treat with sodium borohydride (0.5 g, 13.3 mmol) at 0° C. Stirthe reaction mixture for 30 min at ambient temperature and quench withwater (30 mL). Extract the reaction mixture with DCM (3×10 mL), combinethe organic extracts and dry over anhydrous Na₂SO₄. Remove the solventto obtain the desired intermediate as a colorless oil (1.9 g, 94%).4-Chloromethyl-benzo[1,3]dioxole: Dissolvebenzo[1,3]dioxol-4-yl-methanol (1.9 g, 12.5 mmol) in thionyl chloride (3mL, 41.1 mmol) and reflux the reaction mixture for 1 h. Concentrate invacuo to obtain the desired intermediate as a yellow oil (1.9 g, 91%)that was used without further purification. GC-MS m/z: 170 (M⁺).4-Methylamino-benzo[1,3]dioxole: Dissolve4-chloromethyl-benzo[1,3]dioxole (1.9 g, 11.1 mmol) in methanol (5 mL),cool the solution to 0° C. and saturate with anhydrous ammonia for 15min. Keep the reaction mixture at 0° C. for 18 h. Evaporate the solventand purify by SCX chromatography to obtain the title compound as ayellow oil (0.6 g, 36%). GC-MS m/z: 151 (M⁺).

Preparation 152 6-Bromomethyl-benzothiazole

Benzothiazole-6-carboxylic acid methyl ester: Add1-methyl-3-nitro-1-nitrosoguanidine (5.0 g, 33.9 mmol) to a mixture ofdiethyl ether (20 mL) and 1N aqueous NaOH (20 mL) at ambienttemperature. Separate the organic layer and add it slowly to a solutionof benzothiazole-6-carboxylic acid (1.0 g, 5.58 mmol) in THF (50 mL) at0° C. Evaporate the solvent to obtain the desired intermediate as ayellow solid (1.1 g, 100%). MS (ES+) m/z: 194 (M+H)⁺.Benzothiazol-6-yl-methanol: Add slowly a solution ofbenzothiazole-6-carboxylic acid methyl ester (0.5 g, 2.59 mmol) inanhydrous THF (10 mL) to a suspension of lithium aluminum hydride (0.1g, 2.85 mmol) in anhydrous THF (20 mL) at −10° C. and stir for 20 min at−10° C. Treat the reaction mixture with 2N aqueous NaOH until a granularprecipitate starts to form and filter through a pad of Celite®.Evaporate the solvent and purify by chromatography on silica gel elutingwith hexane/EtOAc (1:0, 9:1, 4:1, 7:3, 3:2 and 1:1) to obtain thedesired intermediate as a yellow oil (0.4 g, 99%). MS (ES+) m/z: 166(M+H)⁺.6-Bromomethyl-benzothiazole: Dissolve benzothiazol-6-yl-methanol (0.4 g,2.55 mmol) in diethyl ether (10 mL) and add slowly a solution ofphosphorus tribromide (0.7 g, 2.55 mmol) in diethyl ether (5 mL). Stirthe reaction mixture for 2 h at ambient temperature, wash with brine,dry the organic phase over anhydrous Na₂SO₄, evaporate the solvent andpurify by chromatography on silica gel eluting with hexane/EtOAc (1:0,9:1 and 4:1) to obtain the title compound as a white solid (0.5 g, 86%).MS (ES+) m/z: 229 (M+H)⁺.

Preparation 153 6-Bromomethyl-2-cyclohexyl-benzothiazole

Cyclohexanecarboximidic acid ethyl ester, hydrochloride: Combinecyclohexanecarbonitrile (1.0 g, 9.20 mmol), ethanol (0.4 g, 9.20 mmol)and 4N hydrogen chloride in dioxane (8 mL) and stir the reaction mixturefor 17 h at ambient temperature. Evaporate the solvent and triturate theresidue with diethyl ether to obtain the desired intermediate as a whitesolid (1.4 g, 80%).2-Cyclohexyl-6-methyl-benzothiazole: Combine2-amino-5-methyl-benzenethiol zinc salt (1.0 g, 2.91 mmol, prepared asdescribed in Synth. Commun. 1980, 10, 167-173), cyclohexanecarboximidicacid ethyl ester hydrochloride (1.1 g, 5.82 mmol), methanol (20 mL) andreflux the reaction mixture for 17 h. Evaporate the solvent and purifyby chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1)to obtain the desired intermediate as a white solid (1.15 g, 85%).6-Bromomethyl-2-cyclohexyl-benzothiazole: Combine2-benzyl-6-methyl-benzothiazole (0.6 g, 2.42 mmol), NBS (0.5 g, 2.54mmol), AIBN (40 mg, 0.24 mmol), carbon tetrachloride (10 mL) and refluxfor 3 h. Cool the reaction mixture to ambient temperature, dilute withchloroform and wash with water. Dry the organic extracts over anhydrousNa₂SO₄, concentrate in vacuo and purify by chromatography on silica geleluting with hexane/EtOAc (1:0 and 9:1) to obtain the title compound asa white solid (0.4 g, 53%). MS (ES+) m/z: 311 (M+H)⁺.

Preparation 154 6-Bromomethyl-2-phenyl-benzothiazole

6-Methyl-2-phenyl-benzothiazole: Combine 2-amino-5-methyl-benzenethiolzinc salt (1.0 g, 2.91 mmol, prepared as described in Synth. Commun.1980, 10, 167-173), ethyl benzimidate hydrochloride (1.1 g, 5.82 mmol),methanol (20 mL), and reflux the reaction mixture for 17 h. Evaporatethe solvent and purify by chromatography on silica gel eluting withhexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate as a whitesolid (1.1 g, 85%). MS (ES+) m/z: 226 (M+H)⁺.6-Bromomethyl-2-phenyl-benzothiazole: Combine6-methyl-2-phenyl-benzothiazole (0.2 g, 0.98 mmol), NBS (0.2 g, 1.02mmol), AIBN (20 mg, 0.10 mmol), carbon tetrachloride (5 mL) and refluxfor 3 h. Cool the reaction mixture to ambient temperature, dilute withchloroform and wash with water. Dry the organic extracts over anhydrousNa₂SO₄, concentrate and purify by chromatography on silica gel elutingwith hexane/EtOAc (1:0, 9:1, 8:2 and 7:3) to obtain the title compoundas a white solid (0.2 g, 69%).

Preparation 155 2-Benzyl-6-bromomethyl-benzothiazole

2-Phenyl-acetimidic acid ethyl ester, hydrochloride: Combine benzylcyanide (1.0 g, 8.50 mmol), ethanol (0.4 g, 8.50 mmol) and 4N hydrogenchloride in dioxane (8 mL) and stir the reaction mixture at ambienttemperature for 17 h. Evaporate the solvent and triturate the residuewith diethyl ether to obtain the desired intermediate as a white solid(1.7 g, 100%).2-Benzyl-6-methyl-benzothiazole: Combine 2-amino-5-methyl-benzenethiolzinc salt (1.0 g, 2.91 mmol, prepared as described in Synth. Commun.1980, 10, 167-173), 2-phenyl-acetimidic acid ethyl ester hydrochloride(1.16 g, 5.82 mmol), methanol (20 mL) and reflux the reaction mixturefor 17 h. Evaporate the solvent and purify by chromatography on silicagel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the desiredintermediate as a white solid (1.0 g, 72%). MS (ES+) m/z: 240 (M+H)⁺.2-Benzyl-6-bromomethyl-benzothiazole: Combine2-benzyl-6-methyl-benzothiazole (0.6 g, 2.51 mmol), NBS (0.5 g, 2.63mmol), AIBN (40 mg, 0.25 mmol), carbon tetrachloride (10 mL) and refluxfor 3 h. Cool the reaction mixture to ambient temperature, dilute withchloroform and wash with water. Dry the combined organic extracts overanhydrous Na₂SO₄, evaporate the solvent and purify by chromatography onsilica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the titlecompound as a white solid (0.2 g, 69%). MS (ES+) m/z: 319 (M+H)⁺.

Preparation 156 5-Bromomethyl-benzoxazole

5-Methyl-benzoxazole: Combine 2-amino-4-methyl-phenol (1.0 g, 8.12mmol), [(dimethylaminomethylene-aminomethylene)dimethylammonium chloride(Gold's reagent) (1.6 g, 9.91 mmol), anhydrous 1,4-dioxane (25 mL) andreflux for 17 h. Cool the reaction mixture to ambient temperature,evaporate the solvent and purify by chromatography on silica gel elutingwith hexane/EtOAc (9:1) to obtain the desired intermediate as a yellowoil (0.7 g, 65%).5-Bromomethyl-benzoxazol: Combine 5-methyl-benzoxazole (0.5 g, 3.75mmol), NBS (0.7 g, 3.93 mmol), AIBN (60 mg, 0.37 mmol), chloroform (10mL) and reflux for 1 h. Cool the reaction mixture to ambienttemperature, dilute with chloroform and wash with water. Dry the organicextracts over anhydrous Na₂SO₄, evaporate the solvent and purify bychromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 4:1and 7:3) to obtain the title compound as a white solid (0.1 g, 13%).

Preparation 157 5-Methylamino-2-phenyl-benzoxazole

2-(Phenyl-benzoxazol-5-ylmethyl)-carbamic acid 2-trimethylsilanyl-ethylester: Combine (2-phenyl-benzoxazol-5-yl)acetic acid (1.0 g, 3.95 mmol),triethylamine (0.5 g, 4.34 mmol), and anhydrous toluene (20 mL), heat toreflux and slowly add diphenylphosphoryl azide (1.2 g, 4.15 mmol) inanhydrous toluene (8 mL). Continue to reflux for 3 h, cool to ambienttemperature, add 2-trimethylsilylethanol (0.9 g, 7.89 mmol) to thereaction mixture and continue to reflux for 3 h. Evaporate the solventand purify by chromatography on silica gel eluting with hexane/EtOAc(1:0, 9:1, 4:1 and 7:3) to obtain the desired intermediate as a yellowsolid (0.4 g, 26%).5-Methylamino-2-phenyl-benzoxazole: Dissolve(2-phenyl-benzoxazol-5-yl-methyl)-carbamic acid 2-trimethylsilanyl-ethylester (0.4, 0.99 mmol) in anhydrous THF (5 mL) and treat with 1Mtetrabutylammonium fluoride in THF (1.5 mL, 1.54 mmol). Heat the mixtureat reflux for 30 min evaporate the solvent and purify by SCXchromatography to obtain the title compound as a yellow oil (0.1 g,27%).

Preparation 158 4-Aminomethyl-1-methylindole

1-Methylindole-4-carbonitrile: Add slowly a solution ofindole-4-carbonitrile (1.0 g, 7.04 mmol) in anhydrous DMF (5 mL) to asuspension of sodium hydride (60% dispersion in mineral oil, 0.6 g, 8.64mmol) in anhydrous DMF (2 nm) at 0° C. and warm the reaction mixture toambient temperature. Add iodomethane (0.7 mL, 10.6 mmol) and stir thereaction for 1 h at ambient temperature. Dilute the reaction mixturewith 1M aqueous NH₄OH (30 mL) and extract with diethyl ether (3×10 mL).Combine the organic extracts, dry over anhydrous Na₂SO₄, concentrate invacuo and purify by chromatography on silica gel eluting withhexane/EtOAc (1:0, 9:1, 4:1 and 7:3) to obtain the desired intermediateas a yellow oil (1.0 g, 87%). GC-MS m/z: 156 (M⁺).4-Aminomethyl-1-methylindole: Dissolve 1-methylindole-4-carbonitrile(1.0 g, 6.18 mmol) in anhydrous THF (10 mL) and add slowly to 1M lithiumaluminum hydride in THF (12.4 mL, 12.37 mmol) at ambient temperature.Heat the reaction mixture at 50° C. for 17 h and cool to ambienttemperature. Quench the reaction mixture with water until a granularprecipitate starts to form and filter through a pad of Celite®.Evaporate the solvent and purify by SCX chromatography to obtain thetitle compound as a yellow oil (0.9 g, 91%). GC-MS m/z: 160 (M*).

Preparation 159 6-Aminomethyl-1-methylindole

1-Methylindole-6-carbonitrile: Add slowly a solution ofindole-6-carbonitrile (1.0 g, 7.04 mmol) in anhydrous DMF (5 mL) to asuspension of sodium hydride (60% dispersion in mineral oil, 0.6 g, 14.1mmol) in anhydrous DMF (2 mL) at 0° C. and warm the reaction mixture toambient temperature. Add iodomethane (0.7 mL, 1.06 mmol) and stir thereaction mixture for 1 h at ambient temperature. Dilute the reactionmixture with 1M aqueous NH₄OH (30 mL) and extract with diethyl ether(3×10 mL). Combine the organic layers, dry over anhydrous Na₂SO₄, removethe solvent and purify by chromatography on silica gel eluting withhexane/EtOAc (1:0, 9:1, 4:1 and 7:3) to obtain the desired intermediateas a yellow oil (1.0 g, 87%). MS (ES+) m/z: 156 (M+H)⁺.6-Aminomethyl-1-methylindole: Dissolve 1-methylindole-6-carbonitrile(0.97 g, 6.18 mmol) in anhydrous THF (10 mL) and add slowly to 1Mlithium aluminum hydride in THF (1.24 mL, 1.24 mmol) at ambienttemperature. Heat the reaction mixture at 50° C. for 17 h and cool toambient temperature. Quench the reaction mixture with water until agranular precipitate starts to form and filter through a pad of Celite®.Evaporate the solvent and purify by SCX chromatography to obtain thetitle compound as a yellow oil (0.9 g, 91%). GC-MS m/z: 160 (M⁺).

Preparation 160 6-Aminomethyl-benzofuran

Dissolve benzofuran-6-carbonitrile (0.5 g, 3.28 mmol) in anhydrous THF(10 mL) and add slowly to 1M lithium aluminum hydride in THF (6.56 mL,6.56 mmol) at ambient temperature. Heat the reaction mixture at 50° C.for 17 h and cool to ambient temperature. Quench the reaction mixturewith water until a granular precipitate starts to form and filterthrough a pad of Celite®g. Evaporate the solvent and purify by SCXchromatography to obtain the title compound as a yellow oil (0.4 g,79%).

Preparation 161 4-Aminomethyl-benzofuran

Benzofuran-4-carbonitrile: Combine 4-bromo-benzofuran (1.0 g, 5.07mmol), copper(I) cyanide (0.9 g, 10.2 mmol), anhydrous DMF (16 ml) andreflux for 17 h. Cool the reaction mixture to ambient temperature, treatwith 50% (v/v) aqueous ethylenediamine (25 mL). Extract the reactionmixture with diethyl ether (3×15 mL), combine the organic extracts, washwith brine (15 mL) and dry over anhydrous Na₂SO₄. Evaporate the solventand purify by chromatography on silica gel eluting with hexane/EtOAc(1:0, 9:1 and 4:1) to obtain the desired intermediate as a colorless oil(0.3 g, 39%).4-Aminomethyl-benzofuran: Dissolve benzofuran-4-carbonitrile (0.3 g,1.96 mmol) in anhydrous THF (5 mL) and add slowly to 1M lithium aluminumhydride in THF (3.91 mL, 3.91 mmol) at ambient temperature. Heat thereaction mixture at 50° C. for 5 h and cool to ambient temperature.Quench the reaction mixture with water until a granular precipitatestarts to form and filter through a pad of Celite®. Evaporate thesolvent and purify by SCX chromatography to obtain the title compound asa brown oil (0.4 g, 79%). GC-MS m/z: 147 (M⁺).

Preparation 162 4-Aminomethyl-benzo[b]thiophene

Add lithium aluminum hydride (1M solution in THF, 7.5 mL) tobenzo[b]thiophene-4-carbonitrile (prepared as described in WO 0168653)(0.6 g, 3.8 mmol) at 0° C. in THF (38 mL). After 17 h at ambienttemperature, cool to 0° C. and add sequentially water (1.89 mL), 2Naqueous NaOH (1.89 mL) and water (2.69 mL). Filter the solids andevaporate the filtrate to obtain the crude amine. Purify by SCXchromatography. Rinse the column with methanol, add a solution of thecrude amine in methanol, wash the column with methanol and then elutewith 1N ammonia in methanol. Concentrate to give the title compound(0.57 g, 93%). GC-MS m/z: 163 (M⁺).

Preparation 163 6-Aminomethyl-benzo[b]thiophene

Benzo[b]thiophen-6-carbonitrile: Heat copper(I) cyanide (0.84 g, 9.4mmol) and 6-bromobenzo[b]thiophene (prepared as described in WO01/23381) (1.0 g, 4.7 mmol) at 160° C. for 13 h. Cool the mixture to 0°C., add 33% aqueous ethylenediamine (20 mL) and dilute with ether. Washthe organic mixture with brine, dry over-Na₂SO₄ and evaporate. Purify bychromatography on silica gel eluting with EtOAc/hexane (0:1 to 1:3) togive the desired intermediate (0.58 g, 78%). GC-MS m/z: 159 (M⁺).6-Aminomethyl-benzo[b]thiophene: Add 1M lithium aluminum hydride in THF(7.3 mL) to benzo[b]thiophene-6-carbonitrile (0.6 g, 3.6 mmol) at 0° C.in THF (36 mL). After 15 h at ambient temperature, cool to 0° C. and addsequentially water (1.82 mL), 2N aqueous NaOH (1.82 mL) and water (2.60mL). Filter the solid and evaporate the filtrate to obtain the crudeamine. Purify by SCX chromatography. Rinse the column with methanol, adda solution of the crude amine in methanol, wash the column with methanoland then elute with 1N ammonia in methanol. Concentrate in vacuo to givethe title compound (0.55 g, 92%).

Preparation 164 8-Bromomethyl-quinoline

Combine 8-methyl-quinoline (1.0 g, 6.99 mmol), NBS (1.3 g, 7.13 mmol),benzoyl peroxide (6.0 mg, 0.03 mmol), carbon tetrachloride (30 mL) andreflux for 17 h. Cool the reaction mixture to ambient temperature andevaporate the solvent. Dissolve the residue in chloroform (30 mL), washthe organic solution with saturated aqueous NaHCO₃ (2×10 mL), brine (10mL) and dry over anhydrous Na₂SO₄. Evaporate the solvent and purify bychromatography on silica gel eluting with DCM to obtain the titlecompound as a white solid (1.3 g, 83%). MS (ES+) m/z: 223 (M+H)⁺.

Preparation 165 2-Aminomethyl-quinoline

Combine quinoline-2-carbonitrile (0.2 g, 1.29 mmol), Raney® 3201 nickel(slurry in water, 0.05 g), 2N ammonia in methanol (10 mL) andhydrogenate at 50 psi for 15 min. Filter the reaction mixture through apad of Celite®, remove the solvent and purify by SCX chromatography toobtain the title compound as a yellow oil (0.2 g, 98%). MS (ES+) m/z:159 (M+H)⁺.

Preparation 166 3-Aminomethyl-quinoline Dihydrochloride

Combine quinoline-3-carbonitrile (1.0 g, 6.49 mmol), 10% Pd/C (0.2 g),5% TFA in methanol (100 mL) and hydrogenate at 30 psi for 2 h. Filterthe reaction mixture through a pad of Celite® and evaporate the solvent.Dissolve the residue in ethanol (10 mL), treat with 1N hydrogen chloridein diethyl ether (5 mL) and allow the mixture to stand at 5° C. for 18h. Filter the precipitate, wash with ethanol and dry under vacuo toobtain the title compound as a white solid (0.6 g, 53%).

Preparation 167 2-Aminomethyl-isoquinoline Dihydrochloride

Combine isoquinoline-3-carbonitrile (1.0 g, 6.49 mmol), 10% Pd/C (0.2g), 5% TFA in methanol (95 mL) and hydrogenate at 30 psi for 17 h.Filter the reaction mixture through a pad of Celite® and evaporate thesolvent. Dissolve the residue in ethanol (10 mL), treat with 1N hydrogenchloride in diethyl ether (5 mL) and allow to stand at 5° C. for 18 h.Filter the precipitate, wash with ethanol and dry under vacuo to obtainthe title compound as a white solid (0.6 g, 55%).

Preparation 168 6-Aminomethyl-quinoline

6-Quinolinecarboxamide: Combine 6-quinolinecarboxylic acid (2.0 g, 11.6mmol), 1,1-carbonyldiimidazol (3.8 g, 23.45 mmol) in DCM (50 mL) andstir at ambient temperature for 1 h. Saturate the reaction mixture withanhydrous ammonia and continue to stir for 1 h. Quench the reactionmixture with water (100 mL) and extract with chloroform (3×50 mL).Combine the organic extracts, dry over anhydrous Na₂SO₄ and evaporatethe solvent to obtain the desired intermediate as a white solid (1.6 g,78%).6-Quinolinecarbonitrile: Dissolve 6-quinolinecarboxamide (1.5 g, 8.95mmol) in DCM (50 mL), add triethylamine (2.7 g, 26.8 mmol) and cool thereaction mixture to 0° C. Add trifluoroacetic acid anhydride (2.4 g,11.16 mmol) to the reaction mixture and stir for 10 min at 0° C. Quenchthe reaction mixture with water (20 mL) and separate the organic layer.Extract aqueous layer with DCM (2×15 mL). Combine the organic extractsand dry over anhydrous Na₂SO₄. Evaporate the solvent to obtain thedesired intermediate as a white solid (1.0 g, 73%). GC-MS m/z: 154 (M⁺).6-Aminomethyl-quinoline: Combine 6-quinolinecarbonitrile (1.0 g, 6.49mmol), Raney® 3201 nickel (slurry in water, 0.2 g), 2N ammonia inmethanol (20 mL) and hydrogenate at 50 psi for 1 h. Filter the reactionmixture through a pad of Celite®, remove the solvent and purify by SCXchromatography to obtain the title compound as a yellow oil (0.8 g,78%).

Preparation 169 (±)-2-(1-Aminoethyl)-5-methylthiophene

(±)-2-(1-Hydroxyethyl)-5-methylthiophene: Add sodium borohydride (270mg, 7.13 mmol) to a solution of 2-acetyl-5-methylthiophene (1.0 g, 7.13mmol) in methanol (40 mL). Stir the mixture for 1 h at room temperature.Remove the solvent in vacuo and partition the residue between water andDCM. Separate the organic phase, dry over Na₂SO₄, filter and concentrateto obtain the desired intermediate as an oil (0.995 g, 98%) that wasused without further purification. GC-MS m/z 142 (M⁺).(±)-2-(1-Azidoethyl)-5-methylthiophene: Add DBU (1.228 g, 1.2 mL, 8.07mmol) to a solution of (−)-2-(1-hydroxyethyl)-5-methylthiophene (0.955g, 6.72 mmol) and diphenylphosphoryl azide (2.22 g, 1.74 mL, 8.07 mmol)in anhydrous toluene. Stir at room temperature for 18 h. Dilute themixture with EtOAc and wash with water and 0.5N aqueous HCl. Dry theorganic phase over Na₂SO₄, filter and concentrate. Purify bychromatography on silica gel eluting with hexane/EtOAc (1:0 and 19:1) toobtain the desired intermediate as an oil (0.875 g, 78%). GC-MS m/z 167(M⁺).(±)-2-(1-Aminoethyl)-5-methylthiophene: Add lithium aluminum hydride (29mg, 0.72 mmol) to a solution of (±)-2-(1-azidoethyl)-5-methylthiophene(100 mg, 0.59 mmol) in anhydrous THF (5 mL). Stir at room temperatureovernight. Work-up the mixture with EtOAc and water. Filter the mixtureover Celite®. Separate and wash the organic phase with brine. Dry overNa₂SO₄, filter and concentrate in vacuo. Purify by SCX chromatography.Rinse with DCM/methanol (1:1), load the crude mixture in methanol andelute sequentially with methanol and 1N ammonia in methanol to obtainthe title compound as an oil (80 mg, 95%). GC-MS m/z 141 (M⁺).

Preparations 170 and 171 1-(5-Phenyl-thiophen-2-yl)ethylamine, Isomers 1and 2

N-[(5-Phenylthiophen-2-yl)-methylene]-2-methylpropanesulfinamide: To asolution of 5-phenyl-2-thiophenecarboxaldehyde (1.25 g, 6.64 mmol) inanhydrous THF (50 mL), add titanium(IV) ethoxide (3.03 g, 2.78 mL, 13.28mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (0.965 g, 7.968 mmol)under nitrogen. Heat the reaction at 80° C. overnight Cool the mixtureto room temperature and dilute with EtOAc. Add water and filter theresulting precipitate over Celite®. Separate and dry the organic phaseover Na₂SO₄, filter and concentrate in vacuo to obtain the desiredintermediate as a yellow solid (1.93 g, 100% yield) that was usedwithout purification.N-[1-(5-Phenylthiophen-2-yl)ethyl]-2-methylpropanesulfinamide (Isomer 1)and N-[1-(5-phenylthiophen-2-yl)ethyl]-2-methylpropanesulfinamide(Isomer 2): Add slowly methyllithium (8.1 mL, 12.92 mmol, 1.6 M solutionin ether) to a solution ofN-[(5-phenylthiophen-2-yl)-methylene]-2-methylpropanesulfinamide (1.883g, 6.46 mmol) in anhydrous THF (50 mL) at −40° C. Warm the reaction to−20° C. and stir for 2 h. Warm to 0° C. and stir for an additional 2 h.Add saturated aqueous NH₄Cl and extract with EtOAc. Dry the organicphase over Na₂SO₄, filter and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (7:3 and 1:1) toobtain N-[1-(5-phenylthiophen-2-yl)ethyl]-2-methylpropanesulfinamide(Isomer 1) (575 mg, 30% yield) andN-[1-(5-phenylthiophen-2-yl)ethyl]-2-methylpropanesulfinamide (Isomer 2)(847 mg, 44% yield).1:5-Phenyl-thiophen-2-yl)ethylamine (Isomer 1, Preparation 170) Add 4Nhydrogen chloride in dioxane (0.837 mL, 3.349 mmol) to a stirredsolution ofN-[1-(5-phenylthiophen-2-yl)ethyl]-2-methylpropanesulfinamide (Isomer 1)(515 mg, 1.675 mmol) in methanol (8 mL) at room temperature. Stir for 2h and remove the solvent in vacuo to obtain a solid that was washed withethyl ether. Dissolve the solid in DCM and wash with saturated aqueousNaHCO₃. Dry the organic phase over Na₂SO₄, filter and concentrate invacuo to obtain the desired intermediate (236 mg, 69% yield).

1-(5-Phenyl-thiophen-2-yl)ethylamine (Isomer 2, Preparation 171) Add 4Nhydrogen chloride in dioxane (1.112 mL, 4.449 mmol) to a stirredsolution ofN-[1-(5-phenylthiophen-2-yl)ethyl]-2-methylpropanesulfinamide (Isomer 2)(684 mg, 2.225 mmol) in methanol (10 mL) at room temperature. Stir for 2h and remove the solvent in vacuo to obtain a solid that was washed withethyl ether. Dissolve the solid in DCM and wash with saturated aqueousNaHCO₃. Dry the organic phase over Na₂SO₄, filter and concentrate invacuo to obtain the desired intermediate (347 mg, 77% yield).

EXAMPLE 496-(2-Benzoylamino-ethylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Dissolve6-(2-amino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(70 mg, 0.208 mmol) in DCM (4 mL). Add benzoyl chloride (24 μL, 0.208mmol), and triethylamine (44 μL, 0.312 mmol) and stir at ambienttemperature for 24 h under nitrogen atmosphere. Dilute with DCM and add1M aqueous HCl. Extract the aqueous layer with DCM. Dry the organiclayer over MgSO₄ and concentrate in vacuo. Purify by chromatography onsilica gel eluting with hexane/EtOAc (1:0, 7:3 and 1:1) to obtain6-(2-benzoylamino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.

Use a method similar to the General Procedure 1-1, using6-(2-benzoylamino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine,to give the free base of the title compound. Use a method similar to theGeneral Procedure 2-2 to give the title compound (77 mg, 90% overall).HPLC: t_(R)=2.64 min (20-80% of Solvent B in 7.5 min. Solvent A: water,0.1% TFA. Solvent B: acetonitrile, 0.1% TFA. Column: C18-Metachem, 5micron, 4.6×50).

Examples 50-52 may be prepared essentially as described in Example 49 byusing6-(2-amino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineor6-(3-amino-propylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate benzoyl chloride. Overall yields and MS (ES+) dataare shown in the Table below.

Yield MS Ex. NH—CO—R n Compound (%) (ES+) 50

27-Chloro-6-[2-(2-fluorobenzoylamino)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 40 362(M + H)⁺ 51

36-(3-Benzoylamino-propylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 90 ND 52

37-Chloro-6-[3-(2-fluorobenzoylamino)-propylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 40 376(M + H)⁺ ND = Not determined

EXAMPLE 537-Chloro-6-{2-[(pyridine-3-carbonyl)-amino]-ethylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Dissolve nicotinic acid (28.2 mg, 0.23 mmol) in DCM (3 mL). Add EDC (40mg, 0.208 mmol), HOBT (28.1 mg, 0.2081 mmol) and stir at ambienttemperature for 10 min. Add6-(2-amino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(70 mg, 0.208 mmol) and stir at ambient temperature for 10 hr. Dilutewith DCM, add water and extract the aqueous layer three times with DCM.Wash combined organic extracts with 1N aqueous NaOH, and brine. Dry theorganic layer over MgSO₄, concentrate in vacuo and purify bychromatography on silica gel eluting with hexane/EtOAc (1:0, 1:1, 3:7and 1:9) to obtain7-chloro-6-{2-[(pyridine-3-carbonyl)-amino]-ethylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.

Use a method similar to the General Procedure 1-1, using7-chloro-6-{2-[(pyridine-3-carbonyl)-amino]-ethylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine,to give the free base of the title compound. Use a method similar to theGeneral Procedure 2-2 to give the title compound as a solid (92 mg,98%). HPLC: t_(R)=1.38 min (20-80% of Solvent B in 7.5 min. Solvent A:water, 0.1% TFA. Solvent B: acetonitrile, 0.1% TFA. Column: C18Metachem; 5 micron, 4.6×50).

EXAMPLE 547-Chloro-6-[3-(3-phenyl-ureido)-propylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Combine phenyl isocyanate (15 μL, 0.137 mmol) and6-(3-amino-propylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(48 mg, 0.137 mmol) in DCM and stir for 16 h. Concentrate, add DCM,filter and collect the solid to obtain7-chloro-6-[3-(3-phenyl-ureido)-propylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(18 mg, 28%).

Use a method similar to the General Procedure 1-1, using7-chloro-6-[3-(3-phenyl-ureido)-propylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine,to give the free base of the title compound. Use a method similar to theGeneral Procedure 2-2 to give the title compound (14 mg, 23%). MS (ES+)m/z: 373 (M+H)⁺.

EXAMPLE 556-(2-Phenoxy-ethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 5-1, using3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(100 mg, 0.23 mmol) and phenoxyethylamine (63 mg, 0.4 mmol) to give,after chromatography on silica gel eluting with hexane/EtOAc (85:15)followed by SCX chromatography,6-(2-phenoxyethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil. MS (ES+) m/z: 379 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect6-(2-phenoxy-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(75 mg, 0.19 mmol). Purify by SCX chromatography to give the free baseof the title compound. Use a method similar to the General Procedure 2-2to give the title compound as a white solid. MS (ES+) m/z: 283 (M+H)⁺.

Examples 56-61 may be prepared essentially as described in Example 55 byusing7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. The yields for the Step 1 (General Procedure5-1) and MS (ES+) data are shown in the Table below.

Yield MS (ES+) Ex. NH—R Compound (%) m/z 56

7-Chloro-6-phenethylamino-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 47 301(M + H)⁺ 57

7-Chloro-6-(3-fluoro-phenethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride55 319(M + H)⁺ 58

7-Chloro-6-[(thiazol-2-yl)methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride21 294(M + H)⁺ 59

7-Chloro-6-[(2-methyl-thiazol-4-yl)methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride16 308(M + H)⁺ 60

7-Chloro-6-(2-pyridin-2-yl-ethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride86 302(M + H)⁺ 61

7-Chloro-6-(2-thiophen-2-yl-ethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride78 ND ND = Not determined

EXAMPLE 627-Chloro-6-[(2-ethoxyethyl)amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.47 mmol) and 2-ethoxyethyl amine (105 μL, 1.0 mmol) to give,after chromatography on silica gel eluting with hexane/EtOAc (95:5) andadditional SCX chromatography,7-chloro-6-[(2-ethoxyethyl)amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(32 mg, 19%). MS (ES+) m/z: 365 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-[(2-ethoxyethyl)amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(30 mg, 0.08 mmol). Purify by SCX chromatography to give the free baseof the title compound. Use a method similar to the General Procedure 2-1to give the title compound as an oil (23.8 mg, 75% over 2 steps). MS(ES+) m/z: 269 (M+H)⁺.

Examples 63-68 may be prepared essentially as described in Example 62 byusing7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. The yields for the Step 1 (General Procedure5-1), optical rotations and MS (ES+) data are shown in the Table below.

Yield MS (ES+) [α]²⁰ _(D) Ex. NH—R Compound (%) m/z. (c, solvent) 63

7-Chloro-6-[2-(1-propoxy)ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 57 283(M + H)⁺ — 64

7-Chloro-6-[2-(2-propoxy)ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 75 283(M + H)⁺ — 65

6-(2-Benzyloxy-ethylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate37 331(M + H)⁺ — 66

(R)-6-(2-Benzyloxy-1-methyl-ethylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate15 345(M + H)⁺ ND 67

(R)-6-(2-Phenoxy-1-methyl-ethylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 15 331(M + H)⁺ +54.7°(c 0.5,CH₃OH) 68

(R)-6-[2-(4-Fluorobenzyloxy)-1-methyl-ethylamino]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 69 363(M + H)⁺ +22.6°(c 0.5,CH₃OH) ND = Not determined

EXAMPLE 69 6-(2-Fluorobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 5-1, using3-(2,2,2-trifluoroacetyl)-6-trifluoromethylsulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(100 mg, 0.26 mmol) and 2-fluorobenzylamine (88 μL, 0.77 mmol) to give,after chromatography on silica gel eluting with hexane/EtOAc (9:1),6-(2-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (45 mg, 48%). MS (ES+) m/z: 367 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect6-(2-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(40 mg, 0.11 mmol). Purify by SCX chromatography to give the free baseof the title compound as a yellow oil (28 mg, 94%). Use a method similarto the General Procedure 2-2 to give the title compound as an off-whitesolid (29 mg, 95%). MS (ES+) m/z: 271 (M+H)⁺.

Example 70 may be prepared essentially as described in Example 69 byusing3-(2,2,2-trifluoroacetyl)-6-trifluoromethylsulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2,6-difluorobenzylamine. The yield for the Step 1 (General Procedure5-1) and MS (ES+) data are shown in the Table below.

Yield MS (ES+) Ex. Structure Compound (%) m/z 70

6-(2,6-Difluorobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride69 289(M + H)⁺

EXAMPLE 717-Chloro-6-(2-fluorobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 5-1 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2-fluorobenzyl amine. Purify by chromatography on silica gel elutingwith hexane/EtOAc (9:1 and 4:1) to give7-chloro-6-(2-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow solid. MS (ES+) m/z: 401 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-(2-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by SCX chromatography to give the free base of the title compoundas a yellow oil. Use a method similar to the General Procedure 2-2 togive the title compound as a light yellow solid. MS (ES+) m/z: 305(M+H)⁺.

Examples 72-80 may be prepared essentially as described in Example 71 byusing7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. MS (ES+) data are shown in the Table below.

MS (ES+) Ex. R Compound m/z 72 3-F 7-Chloro-6-(3-fluorobenzylamino)- 3052,3,4,5-tetrahydro-1H-benzo[d]azepine (M + H)⁺ Hydrochloride 73 4-F7-Chloro-6-(4-fluorobenzylamino)- 3052,3,4,5-tetrahydro-1H-benzo[d]azepine (M + H)⁺ Hydrochloride 74 2,3-diF7-Chloro-6-(2,3-difluorobenzylamino)- 3232,3,4,5-tetrahydro-1H-benzo[d]azepine (M + H)⁺ Hydrochloride 75 3,4-diF7-Chloro-6-(3,4-difluorobenzylamino)- 3232,3,4,5-tetrahydro-1H-benzo[d]azepine (M + H)⁺ Hydrochloride 76 3,5-diF7-Chloro-6-(3,5-difluorobenzylamino)- 3232,3,4,5-tetrahydro-1H-benzo[d]azepine (M + H)⁺ Hydrochloride 773,4,5-triF 7-Chloro-6-(3,4,5- 341 trifluorobenzylamino)-2,3,4,5- (M +H)⁺ tetrahydro-1H-benzo[d]azepine Hydrochloride 78 3-CF₃7-Chloro-6-(3-trifluoromethyl- 355 benzylamino)-2,3,4,5-tetrahydro-1H-(M + H)⁺ benzo[d]azepine Hydrochloride 79 3,5-diCF₃ 7-Chloro-6-[3,5- 423bis(trifluoromethyl)benzylamino]- (M + H)⁺2,3,4,5-tetrahydro-1H-benzo[d]azepine Hydrochloride 80 4-O(CH₂)₂N(CH₃)₂7-Chloro-6-{4-[2-(N,N- 374 dimethylamino)ethoxy]benzylamino}- (M + H)⁺2,3,4,5-tetrahydro-1H-benzo[d]azepine Hydrochloride

EXAMPLE 816-(4-tert-Butylbenzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(300 mg, 0.7 mmol) with 4-(tert-butyl)benzyl amine (375 μL, 2.1 mmol).Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5)followed by SCX chromatography to give6-(4-tert-butylbenzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil (240 mg, 78%). MS (ES+) m/z: 439 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect6-(4-tert-butylbenzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(235 mg, 0.54 mmol). Purify by SCX chromatography to give the free baseof the title compound (161 mg, 87%). Use a method similar to the GeneralProcedure 2-1 to give the title compound as an off-white gum (190 mg,88%). MS (ES+) m/z: 343 (M+H)⁺.

Examples 82-88 may be prepared essentially as described in Example 81 byusing7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. MS (ES+) data are shown in the Table below

MS (ES+) Ex. R Compound m/z 82 3-t-Bu6-(3-tert-Butylbenzylamino)-7-chloro- 3432,3,4,5-tetrahydro-1H-benzo[d]azepine (M + H)⁺ Succinate 83 4-OCF₃7-Chloro-6-(4-trifluoromethoxy- 371 benzylamino)-2,3,4,5-tetrahydro-1H-(M + H)⁺ benzo[d]azepine Succinate 84 4-F,3-CF₃ 7-Chloro-6-[(4-fluoro-3-373 trifluoromethyl)benzylamino]-2,3,4,5- (M + H)⁺tetrahydro-1H-benzo[d]azepine Succinate 85 4-F,3-OCH₃7-Chloro-6-[(4-fluoro-3- 321 methoxy)benzylamino]-2,3,4,5- (M + H)⁺tetrahydro-1H-benzo[d]azepine Succinate 86 4-Ph7-Chloro-6-(4-phenylbenzylamino)- 3632,3,4,5-tetrahydro-1H-benzo[d]azepine (M + H)⁺ Succinate 87 4-OPh7-Chloro-6-(4-phenoxy-benzylamino)- 3792,3,4,5-tetrahydro-1H-benzo[d]azepine (M + H)⁺ Succinate 88 4-SO₂CH₃7-Chloro-6-(4-methanesulfonyl- 365 benzylamino)-2,3,4,5-tetrahydro-1H-(M + H)⁺ benzo[d]azepine Succinate

EXAMPLE 897-Chloro-6-(4-cyanobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1 to react7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(504 mg, 1.2 mmol), 4-cyanobenzylamine (476 mg, 3.6 mmol), palladium(II)acetate (29 mg, 0.1 mmol), BINAP (148 mg, 0.2 mmol) and cesium carbonate(540 mg, 1.7 mmol) in toluene (5 mL). Purify by chromatography on silicagel eluting with isohexane/EtOAc (1:0 to 1:1) to give7-chloro-6-(4-cyanobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a white gum (108 mg, 22%). MS (ES+) m/z: 408 (M+H)⁺.

Use a method similar to the General Procedure 1-2 to deprotect7-chloro-6-(4-cyanobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(98 mg, 0.2 mmol). Purify by preparative liquid chromatography elutingwith a gradient of water/acetonitrile (19:1 to 1:19) to give the freebase of the title compound (31 mg, 42%). MS (ES+) m/z: 312 (+H)⁺. Use amethod similar to the General Procedure 2-1, using7-chloro-6-(4-cyanobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(31 mg, 0.1 mmol) to give the title compound as a beige solid (41 mg,95%). MS (ES+) m/z: 312 (M+H)⁺.

EXAMPLE 907-Chloro-6-(3-phenyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.3 g, 0.706 mmol) with 3-phenyl-benzylamine (0.388 g, 2.117 mmol)using palladium(II) acetate (32 mg, 0.141 mmol),tris(dibenzylideneacetone)dipalladium(0) (65 mg, 0.070 mmol), BINAP (264mg, 0.424 mmol) and cesium carbonate (460 mg, 1.412 mmol) in toluene (12mL). Purify by chromatography on silica gel eluting with hexane/EtOAc(1:0, 19:1) to give7-chloro-6-(3-phenyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (0.257 g, 79%). MS (ES+) m/z: 459 (M+H)⁺.

Use a method similar to the General Procedure 1-2, using7-chloro-6-(3-phenyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(237 mg, 0.516 mmol), to give the free base of the title compound as anoil (188 mg, 100%) that was used without further purification.

Use a method similar to the General Procedure 2-1, using7-chloro-6-(3-phenyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(188 mg, 0.518 mmol) to give the title compound as a white solid (191mg, 77%). MS (ES+) m/z: 363 (M+H)⁺.

EXAMPLE 917-Chloro-6-(4-chlorobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(700 mg, 1.6 mmol) with 4-chlorobenzylamine (354 mg, 2.5 mmol). Purifyby chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1)and then SCX chromatography to give7-chloro-6-(4-chlorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(459 mg, 69%). MS (ES+) m/z: 417 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-[1-(4-chlorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by chromatography on silica gel eluting with DCM/2M ammonia inmethanol (95:5) to give the free base of the title compound. MS (ES+)m/z: 321 (M+H)⁺. Use a method similar to the General Procedure 2-1 toobtain the title compound.

Examples 92-98 may be prepared essentially as described in Example 91 byusing7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. The yields for the Step 1 (General Procedure5-3) and MS (ES+) data are shown in the Table below.

Yield MS (ES+) Ex. R Compound (%) m/z 92 3-Cl 7-Chloro-6-(3- 45 321chlorobenzylamino)-2,3,4,5- (M + H)⁺ tetrahydro-1H-benzo[d]azepineSuccinate 93 3-Cl,4-F 7-Chloro-6-(3-chloro-4-fluoro- 90 339benzylamino)-2,3,4,5-tetrahydro- (M + H)⁺ 1H-benzo[d]azepine Succinate94 2-Cl,4-F 7-Chloro-6-(2-chloro-4-fluoro- 75 339benzylamino)-2,3,4,5-tetrahydro- (M + H)⁺ 1H-benzo[d]azepine Succinate95 3-OCH₃ 7-Chloro-6-(3-methoxy- 84 316 benzylamino)-2,3,4,5-tetrahydro-(M + H)⁺ 1H-benzo[d]azepine Succinate 96 2-F,4-CH₃7-Chloro-6-(2-fluoro-4-methyl- 53 319 benzylamino)-2,3,4,5-tetrahydro-(M + H)⁺ 1H-benzo[d]azepine Succinate 97 3-OCF₃7-Chloro-6-(3-trifluoromethoxy- 85 371 benzylamino)-2,3,4,5-tetrahydro-(M + H)⁺ 1H-benzo[d]azepine Succinate 98 3-Cl, 7-Chloro-6-(3-chloro-4-100  351 4-OCH₃ methoxy-benzylamino)-2,3,4,5- (M + H)⁺tetrahydro-1H-benzo[d]azepine Succinate

Examples 99-106 may be prepared essentially as described in Example 91by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. The yields for the Step 1 (General Procedure5-3) and MS (ES+) data are shown in the Table below.

Yield MS (ES+) Ex. R Compound (%) m/z  99

7-Chloro-6-(4-benzyloxy-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 87 393(M + H)⁺ 100

7-Chloro-6-[4-(3,3-dimethyl-2-oxo-butoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate20 401(M + H)⁺ 101

7-Chloro-6-[4-(2,2-dimethylpropoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 23 373(M + H)⁺ 102

7-Chloro-6-[4-(2-cyclohexylethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 61 413(M + H)⁺ 103

7-Chloro-6-[4-(1H-pyrazol-1-yl)benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 36 353(M + H)⁺ 104

7-Chloro-6-[4-(pyridin-3-yloxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 42 380(M + H)⁺ 105

6-(4-Benzylthio-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 21 409(M + H)⁺

EXAMPLE 1067-Chloro-6-(2-fluoro-4-phenoxy-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Using a method similar to the General Procedure 5-3, couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.1 g, 2.5 mmol) with 2-fluoro-4-phenoxy-benzylamine (550 mg, 2.5mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc(9:1) and then SCX chromatography to obtain7-chloro-6-(2-fluoro-4-phenoxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.MS (ES+) m/z: 493 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-(2-fluoro-4-phenoxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by chromatography on silica gel eluting with DCM/2M ammonia inmethanol (95:5) to give the free base of the title compound (468 mg, 47%overall). MS (ES+) m/z: 397 (M+H)⁺. Use a method similar to the GeneralProcedure 2-1 to obtain the title compound.

EXAMPLE 1077-Chloro-6-[2-fluoro-4-(3′-fluorophenoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the Example 106, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(426 mg, 1.0 mmol) and 2-fluoro-4-(3′-fluorophenoxy)-benzylamine (340mg, 1.4 mmol) to give the free base of the title compound (162 mg, 39%).MS (ES+) m/z: 415 (M+H)⁺. Use a method similar to the General Procedure2-1 to obtain the title compound.

Examples 108-121 may be prepared essentially as described in Example 107by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. The yields for the Step 1 (General Procedure5-3) and MS (ES+) data are shown in the Table below.

Yield MS (ES+) Ex. R Compound (%) m/z 108 2-F7-Chloro-6-[4-(2′-fluorophenoxy)- 44 397benzylamino]-2,3,4,5-tetrahydro-1H- (M + H)⁺ benzo[d]azepine Succinate109 3-F 7-Chloro-6-[4-(3′-fluorophenoxy)- 23 397benzylamino]-2,3,4,5-tetrahydro-1H- (M + H)⁺ benzo[d]azepine Succinate110 4-F 7-Chloro-6-[4-(4′-fluorophenoxy)- 50 397benzylamino]-2,3,4,5-tetrahydro-1H- (M + H)⁺ benzo[d]azepine Succinate111 3-Cl 7-Chloro-6-[4-(3′-chlorophenoxy)- 45 413benzylamino]-2,3,4,5-tetrahydro-1H- (M + H)⁺ benzo[d]azepine Succinate112 3,5-diF 7-Chloro-6-[4-(3′,5′- 36 415 difluorophenoxy)-benzylamino]-(M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate 113 4-CH₃7-Chloro-6-[4-(4′-methylphenoxy)- 54 393benzylamino]-2,3,4,5-tetrahydro-1H- (M + H)⁺ benzo[d]azepine Succinate114 3-CH₃ 7-Chloro-6-[4-(3′-methylphenoxy)- 45 393benzylamino]-2,3,4,5-tetrahydro-1H- (M + H)⁺ benzo[d]azepine Succinate115 2-CH₃ 7-Chloro-6-[4-(2′-methylphenoxy)- 54 393benzylamino]-2,3,4,5-tetrahydro-1H- (M + H)⁺ benzo[d]azepine Succinate116 3-^(i)Pr 7-Chloro-6-[4-(3′- 49 421 isopropylphenoxy)-benzylamino]-(M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate 117 2-^(i)Pr7-Chloro-6-[4-(2′- 40 421 isopropylphenoxy)-benzylamino]- (M + H)⁺2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate 118 2-CN7-Chloro-6-[4-(2′-cyanophenoxy)- 79 404benzylamino]-2,3,4,5-tetrahydro-1H- (M + H)⁺ benzo[d]azepine Succinate119 3-CN 7-Chloro-6-[4-(3′-cyanophenoxy)- 37 404benzylamino)-2,3,4,5-tetrahydro-1H- (M + H)⁺ benzo[d]azepine Succinate120 2-CF₃ 7-Chloro-6-[4-(2′-trifluoromethyl- 30 447phenoxy)-benzylamino]-2,3,4,5- (M + H)⁺ tetrahydro-1H-benzo[d]azepineSuccinate 121 3-CF₃ 7-Chloro-6-[4-(3′-trifluoromethyl- 37 447phenoxy)-benzylamino]-2,3,4,5- (M + H)⁺ tetrahydro-1H-benzo[d]azepineSuccinate

EXAMPLE 1227-Chloro-6-[4-(3′-cyanobenzyloxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Mix7-chloro-6-(4-hydroxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(150 mg, 0.38 mmol), 3-cyanobenzyl bromide (90 mg, 0.46 mmol), powderedpotassium carbonate (105 mg, 0.76 mmol), powdered potassium iodide (6.6mg, 0.04 mmol) and acetone (30 mL). Stir and heat to reflux undernitrogen for 16 hr. Dilute with acetone, filter, concentrate in vacuoand purify by chromatography on silica gel eluting with hexane/EtOAc(1:0 and 4:1) to obtain7-chloro-6-[4-(3′-cyanobenzyloxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(72.4 mg, 37%). MS (ES+) m/z 514 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-[4-(3′cyanobenzyloxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by chromatography on silica gel eluting with DCM/2M ammonia inmethanol (95:5) to give the free base of the title compound (42 mg,71%). MS (ES+) m/z: 418 (M+H)⁺. Use a method similar to the GeneralProcedure 2-1 to obtain the title compound.

Examples 123-126 may be prepared essentially as described in Example 122by using7-chloro-6-(4-hydroxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate bromide. Overall yields and MS (ES+) data are shownin the Table below.

MS Yield (ES+) Ex. O—R Compound (%) m/z 123

7-Chloro-6-[4-(3′-fluorobenzyloxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 75 411(M + H)⁺ 124

7-Chloro-6-[4-(2-oxo-2-phenyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate45 421(M + H)⁺ 125

7-Chloro-6-[4-(2-oxo-2-(4-fluorophenyl)-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 17 439(M + H)⁺ 126

7-Chloro-6-[4-(2-oxo-2-piperidin-1-yl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 44 428(M + H)⁺

EXAMPLE 1277-Chloro-6-[3-chloro-4-(3,3-dimethyl-2-oxo-butoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 4-1 to react7-chloro-6-(3-chloro-4-hydroxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(438 mg, 1.01 mmol) and 1-bromopinacolone (217 mg, 1.21 mmol). Purify bychromatography on silica gel eluting with EtOAc/hexane (1:4) to give7-chloro-6-[3-chloro-4-(3,3-dimethyl-2-oxo-butoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil (441 mg, 82%). MS (ES+) m/z: 531 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-[3-chloro-4-(3,3-dimethyl-2-oxo-butoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(441 mg, 0.83 mmol). Purify by chromatography on silica gel eluting withDCM/2M ammonia in methanol (93:7) to give the free base of the titlecompound (278 mg, 95%). MS (ES+) m/z: 435 (M+H)⁺. Use a method similarto the General Procedure 2-1 to give the title compound.

EXAMPLE 1287-Chloro-6-(3-chloro-4-benzyloxy-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

The title compound may be prepared essentially as described in Example127, using7-chloro-6-(3-chloro-4-hydroxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand benzyl bromide (64%). MS (ES+) m/z: 427 (M+H)⁺.

EXAMPLE 129(±)-7-Chloro-6-[4-(1-phenyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3, to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(851 mg, 2.0 mmol) and (±)-4-(1-phenyl-ethoxy)-benzylamine (721 mg, 2.6mmol). Purify by chromatography on silica gel eluting with EtOAc/hexane(1:8) to give(±)-7-chloro-6-[4-(1-phenyl-ethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(702 mg, 69%). MS (ES+) m/z: 503 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect(±)-7-chloro-6-[4-(1-phenyl-ethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(702 mg, 1.40 mmol). Purify by chromatography on silica gel eluting withDCM/2M ammonia in methanol (92:8) to give the free base of the titlecompound (368 mg, 65%). MS (ES+) m/z: 407 (M+H)⁺. Use a method similarto the General Procedure 2-1 to obtain the title compound.

EXAMPLES 130 AND 131(−)-7-Chloro-6-[4-(1-phenyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate and(+)-7-Chloro-6-[4-(1-phenyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Separate the two enantiomers of Example 129 by chiral HPLC [ChiralcelOJ-H column, acetonitrile/methanol (20:80) with 0.2% DMEA; flow rate 1mL/min; Isomer 1: t_(R)=5.0 min, Isomer 2: t_(R)=60.5 min].

Use a method similar to the General Procedure 2-1 to prepare thesuccinate of each enantiomer:(−)-7-chloro-6-[4-(1-phenyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate, [α]²⁰ _(D) −17.4° (c 0.5, CH₃OH), and(+)-7-chloro-6-[4-(1-phenyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate, [α]²⁰ _(D) +18.2° (c 0.5, CH₃OH).

EXAMPLE 1327-Chloro-6-[4-(3,3-dimethylbutoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineMesylate

Use a method similar to the General Procedure 5-3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(426 mg, 1.0 mmol) and 4-(3,3-dimethylbutoxy)-benzylamine (325 mg, 1.5mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc(1:0 and 9:1) and then SCX chromatography to obtain7-chloro-6-[4-(3,3-dimethylbutoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.MS (ES+) m/z: 483 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-[4-(3,3-dimethylbutoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by chromatography on silica gel eluting with DCM/2M ammonia inmethanol (95:5) to give the free base of the title compound (161 mg, 42%overall). MS (ES+) m/z: 387 (M+H)⁺. Use a method similar to the GeneralProcedure 2-4 to obtain the title compound.

EXAMPLE 1337-Chloro-6-(4-cyclohexylmethoxy-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineMesylate

The title compound may be prepared essentially as described in Example132, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4-cyclohexylmethoxy-benzylamine (27% yield, MS (ES+) m/z 399(M+H)⁺).

EXAMPLE 1347-Chloro-6-(3-pyrrolidinyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(300 mg, 0.7 mmol) and 3-(pyrrolidin-1-yl)benzylamine (300 mg, 1.7 mmol)to give, after chromatography on silica gel eluting with hexane/EtOAc(19:1, 9:1, 4:1 and 3:2),7-chloro-6-(3-pyrrolidinyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (195 mg, 62%). MS (ES+) m/z: 452 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-(3-pyrrolidinyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(195 mg, 0.43 mmol). Purify by SCX chromatography to give the free baseof the title compound (136 mg, 89%). Use a method similar to the GeneralProcedure 2-1, using7-chloro-6-(3-pyrrolidinyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(130 mg, 0.37 mmol), to give the title compound as an off-white gum (111mg, 61%). MS (ES+) m/z: 356 (M+H)⁺.

EXAMPLE 1356-(4-Methoxybenzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a similar method to the General Procedure 1-1, using6-(4-methoxybenzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.1 g, 0.24 mmol) to give the free base of the title compound. Use asimilar method to the General Procedure 2-2 to give the title compound(75 mg, 80%). HRMS calcd for C₁₈H₂₁ClN₂O 317.1421, found 317.1410.

EXAMPLE 1367-Chloro-6-[4-(2,2,3,3-tetrafluoropropoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(500 mg, 1.2 mmol) with 4-(2,2,3,3-tetrafluoropropoxy)-benzylamine (835mg, 3.5 mmol) in toluene (10 mL). Purify by chromatography on silica geleluting with hexane/EtOAc (10:1, 5:1 and 3:1) followed by SCXchromatography [pre-wash column with methanol followed by DCM, loadmaterial dissolved in DCM, then elute with DCM/2M ammonia in methanol(1:1) and concentrate in vacuo] to obtain7-chloro-6-[4-(2,2,3,3-tetrafluoropropoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(600 mg, 99%).

Use a method similar to the General Procedure 1-3 to deprotect7-chloro-6-[4-(2,2,3,3-tetrafluoropropoxy)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(600 mg, 1.2 mmol). Purify by chromatography on silica gel eluting withDCM/2M ammonia in methanol (99:1 to 90:10) to give the free base of thetitle compound. Use a method similar to the General Procedure 2-1 togive the title compound (390 mg, 62%). MS (ES+) m/z: 417 (M+H)⁺.

Examples 137-138 may be prepared essentially as described in Example 136by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

MS Yield (ES+) Ex. O—R Compound (%) m/z 137

7-Chloro-6-[4-(2,2,3,3,3-pentafluoropropoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate45 435(M + H)⁺ 138

7-Chloro-6-[4-(2,2,2-trifluoro-1,2-dimethyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate66 413(M + H)⁺

EXAMPLES 139 AND 140(−)-7-Chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate and(+)-7-Chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(500 mg, 1.2 mmol) with(±)-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzylamine (515 mg, 2.3 mmol)in toluene (10 mL). Purify by chromatography on silica gel eluting withhexane/EtOAc (10:1, 5:1 and 3:1) followed by SCX chromatography[pre-wash column with methanol followed by DCM, load material dissolvedin DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentratein vacuo] to give(±)-7-chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(530 mg, 90%). GC-MS m/z: 494 (M⁺).

Use a method similar to the General Procedure 1-3 to deprotect(±)-7-chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(520 mg, 1.1 mmol). Purify by chromatography on silica gel eluting withDCM/2M ammonia in methanol (99:1 to 90:10) to give(±)-7-chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Use a method similar to the General Procedure 2-1 to obtain(±)-7-chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate.

Separate the two enantiomers of(±)-7-chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate by normal phase chiral chromatography (Chiralpak AD 8×30 cm,elute with 85:15 heptane/3A ethanol with 0.2% DMEA).

Use a method similar to the General Procedure 2-1 to obtain(−)-7-chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate [137 mg, 71% recovery, 980% ee (Chiralpak AD, 4.6×150 mm,eluent: 85:15 heptane/isopropanol with 0.2% DMEA, 0.6 mL/min)]. MS (ES+)m/z: 399 (M+H)⁺. [α]²⁰ _(D) −7.9° (c 0.5, MeOH).

Use a method similar to the General Procedure 2-1 to obtain(+)-7-chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate [133 mg, 69% recovery, 97% ee (Chiralpak AD, 4.6×150 mm,eluent: 85:15 heptane/isopropanol with 0.2% DMEA, 0.6 mL/min)]. MS (ES+)m/z: 399 (M+H)⁺. [α]²⁰ _(D) +9.2° (c 0.5, MeOH).

EXAMPLE 1416-(4-Acetyl-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.47 mmol) with 4-(2-methyl-[1,3]dioxolan-2-yl)-benzylamine(prepared by following the procedure described in J. Med. Chem. 1978,21, 507) (182 mg, 0.94 mmol). Purify by chromatography on silica geleluting with hexane/EtOAc (1:0, 19:1 and 9:1) to give6-{4-(2-methyl-[1,3]dioxolan-2-yl)-benzylamino}-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (150 mg, 68%). GC-MS m/z 468 (M⁺).

Dissolve6-{4-(2-methyl-[1,3]dioxolan-2-yl)benzylamino}-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(150 mg, 0.32 mmol) in methanol (5 mL) and add 1N aqueous HCl (1 mL).Stir the solution at ambient temperature for 2 h. Remove the solvent,dissolve the residue in DCM and wash with saturated aqueous NaHCO₃. Drythe organic phase over Na₂SO₄, filter and concentrate. Purify bychromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 17:3and 4:1) to obtain6-(4-acetyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (107 mg, 79%). GC-MS m/z/z 424 (M⁺).

Use a method similar to the General Procedure 1-2, using6-(4-acetyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(100 mg; 0.23 mmol), to give the free base of the title compound as anoil (76 mg, 99%) that was used without further purification.

Use a method similar to the General Procedure 2-1, using6-(4-acetyl-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(76 mg, 0.23 mmol), to give the title compound as a white solid (102 mg,97%). MS (ES+) m/z: 329 (M+H)⁺.

EXAMPLE 1426-(3-Acetylbenzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to Example 141, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 3-(2-methyl-[1,3]dioxolan-2-yl)-benzylamine (prepared by followingthe procedure described in J. Med. Chem. 2000, 43, 3315), to give thetitle compound as a solid. MS (ES+) m/z: 329 (M+H)⁺.

EXAMPLE 1437-Chloro-6-[4-(1-hydroxyiminoethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Add hydroxylamine hydrochloride (19 mg, 0.27 mmol) and pyridine (0.04mL, 0.54 mmol) to a solution of6-(4-acetylbenzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(115 mg, 0.27 mmol) in ethanol (10 mL). Heat the mixture to reflux for 2h. Remove the solvent in vacuo and partition the residue between DCM and0.1N aqueous HCl. Dry the organic phase over Na₂SO₄, filter andconcentrate. Dissolve the oil into the minimum amount of ether and addhexane to precipitate the solid. Filter to obtain7-chloro-6-[4-(1-hydroxyiminoethyl)-benzylamino]3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a solid (12 mg, 94%) that was used without further purification. MS(ES+) m/z: 440 (M+H)⁺.

Use a method similar to the General Procedure 1-2, using7-chloro-6-[4-(1-hydroxyiminoethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(100 mg, 0.23 mmol), to give7-chloro-6-[4-(1-hydroxyiminoethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (61 mg, 78%) that was used without ether purification.

Use a method similar to the General Procedure 2-1, using7-chloro-6-[4-(1-hydroxyiminoethyl)benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(58 mg, 0.17 mmol) to give the title compound as a white solid (68 mg,87%). MS (ES+) m/z: 344 (M+H)⁺.

EXAMPLE 1446-(4-Benzoyl-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(272 mg, 0.64 mmol) with 4-(aminomethyl)benzophenone (prepared byfollowing the procedure described in J. Biol. Chem. 1993, 268 (19),14230) (270 mg, 1.3 mmol). Purify by chromatography on silica geleluting with hexane/EtOAc (1:0, 9:1, 17:3 and 4:1) to give6-(4-benzoyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (300 mg, 96%).

Use a method similar to the General Procedure 1-2, using6-(4-benzoyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(80 mg, 0.16 mmol), to give6-(4-benzoyl-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (47 mg, 73%) that was used without further purification.

Use a method similar to the General Procedure 2-1, using6-(4-benzoyl-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(45 mg, 0.11 mmol), to give the title compound as a white solid (37 mg,63%). MS (ES+) m/z: 391 (M+H)⁺.

EXAMPLE 1457-Chloro-6-[4-(1-hydroxyiminobenzyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Add hydroxylamine hydrochloride (52 mg, 0.75 mmol) and pyridine (0.1 mL)to a solution of6-(4-benzoyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(91 mg, 0.19 mmol) in ethanol (10 mL). Heat the mixture to refluxovernight. Remove the solvent in vacuo and partition the residue betweenDCM and 0.1N aqueous HCl. Dry the organic phase over Na₂SO₄, filter andconcentrate. Purify by chromatography on silica gel eluting withhexane/EtOAc (1:0, 4:1 and 3:1) to give7-chloro-6-[4-(1-hydroxyiminobenzyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a mixture of E/Z isomers (93 mg, 99%).

Use a method similar to the General Procedure 1-2, using7-chloro-6-[4-(1-hydroxyiminobenzyl)benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(97 mg, 0.19 mmol), to give7-chloro-6-[4-(1-hydroxyiminobenzyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (68 mg, 87%) that was used without further purification.

Use a method similar to the General Procedure 2-1, using7-chloro-6-[4-(1-hydroxyiminobenzyl)benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(65 mg, 0.16° mmol), to give the title compound as a white solid (67 mg,80%). MS (ES+) m/z: 406 (M+H)⁺.

EXAMPLE 1467-Chloro-6-[4-(pyridin-4-yl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(178 mg, 0.426 mmol) and a solution of 4-(pyridin-4-yl)-benzylamine (116mg, 0.63 mmol) in THF/toluene (1:1, 8 mL). Purify by chromatography onsilica gel eluting with hexane/EtOAc (1:0, 7:3 and 1:1) to give7-chloro-6-[4-(4-pyridin-4-yl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (120 mg, 63%). MS (ES+) m/z: 460 (M+H)⁺.

Use a method similar to the General Procedure 1-2, using7-chloro-6-[1-(pyridin-4-yl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(153 mg, 0.33 mmol), to give7-chloro-6-[4-(pyridin-4-yl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (110 mg, 91%) that was used without further purification. Usea method similar to the General Procedure 2-1, using7-chloro-6-[pyridin-4-yl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(105 mg, 0.289 mmol) to give the title compound as a white solid (123mg, 88%). MS (ES+) m/z: 364 (M+H)⁺.

Examples 147-149 may be prepared essentially as described in Example 146by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

MS Yield (ES+) Ex. NH—R Compound (%) m/z 147

7-Chloro-6-[4-(pyridin-2-yl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 32 364(M + H)⁺ 148

7-Chloro-6-[4-(1,2,3-thiadiazol-4-yl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 23 371(M + H)⁺ 149

7-Chloro-6-[4-(2-methylthiazol-4-yl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 22 384(M + H)⁺

EXAMPLE 150(−)-7-Chloro-6-[4-(4-phenyl-4,5-dihydro-1H-imidazol-2-yl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Mix7-chloro-6-(4-cyanobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.49 mmol, 1.0 equiv.), 1-(R)-phenyl-ethane-1,2-diamine (600mg, 4.4 mmol, prepared as described in J. Org. Chem. 1997, 62, 3586) andp-toluenesulfonic acid monohydrate (102 mg, 0.53 mmol) in a sealed tubeequipped with a magnetic stirrer. Heat the mixture to 200° C. for 16 h.Cool the mixture to ambient temperature. Dilute with DCM (50 mL) andwash with saturated aqueous NaHCO₃ (10 mL). Collect the organic fractionand concentrate in vacuo. Purify by chromatography on silica gel elutingwith DCM/2M ammonia in methanol (98:2 to 80:20).

Use a method similar to the General Procedure 2-3 to give title compoundas the hydrochloride. Use reverse phase HPLC [Column: Symmetry C18,10×300 mm, flow 25 mL/min, water with 0.1% TFA/Acetonitrile (9:1 to2:3)] followed by SCX chromatography to obtain the free base of thetitle compound. Use a method similar to the General Procedure 2-3 toobtain the title compound (38 mg, 16%). MS (ES+) m/z: 431 (M+H)⁺. [α]²⁰_(D) −20° (c 0.5, MeOH).

EXAMPLE 1517-Chloro-6-[4-(1-methyl-1H-imidazol-2-yl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(455 mg, 1.1 mmol) with 4-(1-methyl-1H-imidazol-2-yl)-benzylamine (240mg, 1.3 mmol) in toluene (8 mL). Purify by chromatography on silica geleluting with hexane/EtOAc (10:1, 5:1 and 3:1) followed by SCXchromatography [pre-wash column with methanol followed by DCM, loadmaterial dissolved in DCM, then elute with DCM/2M ammonia in methanol(1:1) and concentrate in vacuo] to obtain7-chloro-6-[4-(1-methyl-1H-imidazol-2-yl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(429 mg, 93%). MS (ES+) m/z: 463 (4+H)⁺.

Use a method similar to the General Procedure 1-3 to deprotect7-chloro-6-[4-(1-methyl-1H-imidazol-2-yl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by chromatography on silica gel eluting with DCM/2M ammonia inmethanol (99:1 to 90:10) to give the free base of the title compound.Use a method similar to the General Procedure 2-1 to give the titlecompound (350 mg, 73%). MS (ES+) m/z: 367 (M+H)⁺.

EXAMPLE 1527-Chloro-6-(4-ethanesulfonyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 5-2, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.2 g, 0.35 mmol) and 4-ethanesulfonyl-benzylamine (0.2 g, 1.06 mmol)to give7-chloro-6-(4-ethanesulfonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil.

Use a method similar to the General Procedure 1-1 to obtain the freebase of the title compound as a yellow oil. Use a method similar to theGeneral Procedure 2-2 to form the hydrochloride salt. Purify by reversephase preparative HPLC (Zorbax SB-Phenyl 21.2×250 mm, 5 micron, 22mL/min of 0.1% HCl in water/acetonitrile (9:1 to 1:1) over 30 min,detector at 230 nm) to obtain the title compound as a white solid (57mg, 36%). MS (ES+) m/z: 379 (M+H)⁺.

EXAMPLE 1537-Chloro-6-[4-(2-propanesulfonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

The title compound may be prepared essentially as described in Example152, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4-(2-propanesulfonyl)-benzylamine (11% yield, MS (ES+) m/z 393(M+H)⁺).

EXAMPLE 1547-Chloro-6-(4-methoxycarbonyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Treat 4-aminomethyl-benzoic acid methyl ester hydrochloride (0.2 g, 0.71mmol) with K₂CO₃ (1.0 g, 0.71 mmol) in a mixture of toluene/water (1:1,2 mL). Separate the organic layer, dry over anhydrous Na₂SO₄ and use asa toluene solution for the next step. Use a method similar to theGeneral Procedure 5-2, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.1 g, 0.24 mmol) and 4-aminomethyl-benzoic acid methyl ester (0.2 g,0.71 mmol) to give7-chloro-6-(4-methoxycarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil.

Use a method similar to the General Procedure 1-1 to obtain the freebase of the title compound as a yellow oil. Use a method similar to theGeneral Procedure 2-1 to obtain the title compound as a white solid (20mg, 18%). MS (ES+) m/z: 345 (M+H)⁺.

EXAMPLE 1556-(4-Carboxy-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Combine7-chloro-6-(4-methoxycarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(70 mg, 0.16 mmol), potassium carbonate (0.87 g, 6.3 mmol), methanol (2mL), water (2 mL) and heat at 50° C. for 3 h. Purify by SCXchromatography to obtain6-(4-carboxy-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil.

Use a method similar to the General Procedure 2-2 to form thehydrochloride salt. Purify by reverse phase preparative HPLC [ZorbaxSB-Phenyl 21.2×250 mm, 5 micron, 22 mL/min of 0.1% HCl inwater/acetonitrile (9:1 to 1:1) over 30 min, detector at 230 nm] toobtain the title compound as a white solid (30 mg, 46%). MS (ES+) m/z:331 (M+H)⁺.

EXAMPLE 1567-Chloro-6-(4-methylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Combine3-(tert-butoxycarbonyl)-6-(4-carboxy-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.1 g, 0.3 mmol), methylamine hydrochloride (31 mg, 0.46 mmol),triethylamine (0.1 g, 0.9 mmol), HATU (0.2 g, 0.5 mmol), anhydrous DMF(3 mL) and stir at ambient temperature for 17 h. Partition the reactionmixture between brine (5 mL) and diethyl ether (5 mL), separate theorganic layer and dry over anhydrous Na₂SO₄. Evaporate the solvent toobtain3-(tert-butoxycarbonyl)-7-chloro-6-(4-methylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (0.1 g, 93%). MS (ES+) m/z: 344 (M+H-Boc)⁺.

Use a method similar to the General Procedure 1-5 and purify the residueby SCX chromatography to obtain the free base of the title compound as ayellow oil. Use a method similar to the General Procedure 2-2 to formthe hydrochloride salt. Purify by reverse phase preparative HPLC [ZorbaxSB-Phenyl 21.2×250 mm, 5 micron, 22 mL/min of 0.1% HCl inwater/acetonitrile (9:1 to 1:1) over 30 min, detector at 230 nm] toobtain the title compound as a white solid (0.9 g, 65%). MS (ES+) m/z:344 (M+H)⁺.

Examples 157-158 may be prepared essentially as described in Example 156by using3-(tert-butoxycarbonyl)-6-(4-carboxy-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

MS Yield (ES+) Ex. R R′ Compound (%) m/z 157 Me Me7-Chloro-6-(4-dimethylcarbamoyl- 51 358 benzylamino)-2,3,4,5-tetrahydro-(M + H)⁺ 1H-benzo[d]azepine Hydrochloride 158 i-Pr H7-Chloro-6-(4-isopropylcarbamoyl- 56 372benzylamino)-2,3,4,5-tetrahydro- (M + H)⁺ 1H-benzo[d]azepineHydrochloride

EXAMPLE 1596-(4-tert-Butylcarbamoyl-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 5-2, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.2 g, 0.35 mmol) and 4-aminomethyl-N-tert-butyl-benzamide (0.2 g, 1.06mmol), to give6-(4-tert-butylcarbamoyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil.

Use a method similar to the General Procedure 1-1 to obtain the freebase of the title compound as a yellow oil. Use a method similar to theGeneral Procedure 2-2 to form the hydrochloride salt and purify byreverse phase preparative HPLC [Zorbax SB-Phenyl 21.2×250 mm, 5 micron,22 mL/min of 0.1% HCl in water/acetonitrile (9:1 to 1:1) over 30 min,detector at 230 nm] to obtain the title compound as a white solid (65mg, 41%). MS (ES+) m/z: 386 (M+H)⁺.

Examples 160-161 may be prepared essentially as described in Example 159by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

MS Yield (ES+) Ex. R R′ Compound (%) m/z 160 t-Bu Me6-(4-tert-Butylcarbamoyl-3-fluoro- 48 404 benzylamino)-7-chloro-2,3,4,5-(M + H)⁺ tetrahydro-1H-benzo[d]azepine Hydrochloride 161 n-Pr Me7-Chloro-6-[3-fluoro-4-(N-methyl- 48 404 N-propyl-carbamoyl)-benzyl-(M + H)⁺ amino]-2,3,4,5-tetrahydro-1H- benzo[d]azepine Hydrochloride

7-Chloro-6-[4-(cyclohexylaminocarbonyl-)-3-fluoro-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to react7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(500 mg, 1.17 mmol) with 4-aminomethyl-N-cyclohexyl-2-fluoro-benzamide(441 mg, 1.76 mmol). Purify by chromatography on silica gel eluting withhexane/EtOAc (20:1, 10:1, 7:1 and 5:1) to give7-chloro-6-[4-(cyclohexylaminocarbonyl-)3-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil.

Use a method similar to the General Procedure 1-3 and purify bychromatography on silica gel eluting with DCM/2M ammonia in methanol(1:0, 20:1. 10:1 and 7:1) followed by reverse phase semi-prep HPLC[SymmetryPrep C18, 7 □m, 19×300 mm column eluting with acetonitrile/0.1%trifluoroacetic acid in water (1:9 to 8:2) at 20 mL/min] and SCXchromatography to give the free base of the title compound.

Use a method similar to the General Procedure 2-1 to give the titlecompound as a yellow solid (97 mg, 15%). MS (ES+) m/z: 430 (M+H)⁺.

EXAMPLE 1637-Chloro-6-[4-(2,2,2-trifluoroethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(250 mg, 0.59 mmol) with4-aminomethyl-N-(2,2,2-trifluoroethyl)-benzamide (273 mg, 1.17 mmol).Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1,10:1, 7:1 and 5:1) to give7-chloro-3-(2,2,2-trifluoroacetyl)-6-[4-(2,2,2-trifluoroethyl-aminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil.

Use a method similar to the General Procedure 1-3 and purify bychromatography on silica gel eluting with DCM/2M ammonia in methanol(1:0, 20:1. 10:1 and 7:1) to give the free base of the title compound.Use a method similar to the General Procedure 2-1 to give the titlecompound as a white solid (191 mg, 61%). MS (ES+) m/z: 412 (M+H)⁺.

Examples 164-177 may be prepared essentially as described in Example 163by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

MS Yield (ES+) Ex. NH—R Compound (%) m/z 164

7-Chloro-6-[4-(3,3,3-trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate38 426(M + H)⁺ 165

7-Chloro-6-[4-(2,2,3,3,3-pentafluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate41 462(M + H)⁺ 166

(±)-7-Chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 46 426(M + H)⁺ 167

(±)-7-Chloro-6-[4-(1-methyl-3,3,3-trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 28 440(M + H)⁺ 168

7-Chloro-6-[4-(cyclopentylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 55 398(M + H)⁺ 169

7-Chloro-6-[4-(cyclohexylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 82 412(M + H)⁺ 170

7-Chloro-6-[4-(cycloheptylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 65 426(M + H)⁺ 171

6-[4-(Benzylaminocarbonyl)-benzylamino]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate33 420(M + H)⁺ 172

7-Chloro-6-[4-(3,4-difluoro-benzylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate55 456(M + H)⁺ 173

7-Chloro-6-[4-(1-methyl-1-phenyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate12 448(M + H)⁺ 174

(±)-7-Chloro-6-[4-(1-methyl-2-phenyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate36 448(M + H)⁺ 175

7-Chloro-6-[4-(p-tolylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 60 420(M + H)⁺ 176

7-Chloro-6-[4-(4-chloro-phenylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate28 440(M + H)⁺ 177

7-Chloro-6-[4-(tetrahydro-pyran-4-yl-aminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate13 414(M + H)⁺

EXAMPLES 178 AND 179(−)-7-Chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate and(+)-7-Chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Dissolve(±)-7-chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(472 mg, 1.11 mmol) in DCM (50 mL) and add di-tert-butyl-dicarbonate(300 mg, 1.34 mmol) and a solution of sodium carbonate (2 g) in water(50 mL). Stir the reaction at room temperature for 2 h then dilute withDCM, wash with water, dry over Na₂SO₄, filter and concentrate. Purify bychromatography on silica gel eluting with hexane/EtOAc (10:1, 5:1 and3:1) to give(±)-3-tert-butoxycarbonyl-7-chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-benzo[d]azepine(330 mg, 57%).

Separate the two enantiomers by chiral HPLC [Chiralpak AD column, 8×30cm, eluting with 0.2% DMEA in heptane/isopropanol (9:1)].

Use a method similar to the General Procedure 1-5 to deprotect the firsteluting compound and purify by SCX chromatography to give(−)-7-chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Use a method similar to the General Procedure 2-1 to give(−)-7-chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate as a white solid (50 mg, 15%). MS (ES+) m/z: 426 (M+H)⁺; [α]²⁰_(D) −3.3° (c 0.5, CH₃OH).

Use a method similar to the General Procedure 1-5 to deprotect thesecond eluting compound and purify by SCX chromatography to give(+)-7-chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Use a method similar to the General Procedure 2-1 to give(+)-7-chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate as a white solid (55 mg, 16%). MS (ES+) m/z: 426 (M+H)⁺; [α]²⁰_(D) +4.4° (c 0.5, CH₃OH).

EXAMPLES 180 AND 181(+)-7-Chloro-6-[4-(1-methyl-3,3,3-trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate and(−)-7-Chloro-6-[4-(1-methyl-3,3,3-trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Dissolve(±)-7-chloro-3-(2,2,2-trifluoroacetyl)-6-[4-(1-methyl-3,3,3-trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(985 mg, 2.24 mmol) in DCM (50 mL) and add di-tert-butyl-dicarbonate(605 mg, 3.36 mmol) and a solution of sodium carbonate (2 g) in water(50 mL). Stir the mixture at room temperature for 1 h then dilute withDCM, wash with water, dry over Na₂SO₄, filter and concentrate. Purify bychromatography on silica gel eluting with hexane/EtOAc (10:1, 5:1 and3:1) to give(±)-3-tert-butoxycarbonyl-7-chloro-6-[4-(1-methyl-3,3,3-trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-benzo[d]azepine.

Separate the two enantiomers by chiral HPLC [Chiralpak AD column, 8×30cm, eluting with heptane/isopropanol/0.2% DMEA in methanol (90:5:5)].

Use a method similar to the General Procedure 1-5 to deprotect the firsteluting compound and purify by SCX chromatography to give(+)-7-chloro-6-[4-(1-methyl-3,3,3-trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine.

Use a method similar to the General Procedure 2-1 to give(+)-7-chloro-6-[4-(1-methyl-3,3,3-trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate as a white solid (186 mg, 15%). MS (ES+) m/z: 440 (M+H)⁺;[α]²⁰ _(D) +6.5° (c 0.5, CH₃OH).

Use a method similar to the General Procedure 1-5 to deprotect thesecond eluting compound and purify by SCX chromatography to give(−)-7-chloro-6-[4-(1-methyl-3,3,3-trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine.

Use a method similar to the General Procedure 2-1 to give(−)-7-chloro-6-[4-(1-methyl-3,3,3-trifluoro-propylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate as a white solid (191 mg, 15%). MS (ES+) m/z: 440 (M+E)⁺;[α]²⁰ _(D) −5.2° (c 0.5, CH₃OH).

EXAMPLE 182(R-(+)-7-Chloro-6-[4-(1-phenyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(250 mg, 0.59 mmol) with (R)-4-aminomethyl-N-(1-phenyl-ethyl)-benzamide(298 mg, 1.17 mmol) in toluene (15 mL). Purify by chromatography onsilica gel eluting with hexane/EtOAc (20:1, 10:1, 7:1 and 5:1) to give(R)-(+)-7-chloro-6-[4-(1-phenyl-ethylcaminocarbonyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil.

Use a method similar to the General Procedure 1-3 and purify bychromatography on silica gel eluting with DCM/2M ammonia in methanol(1:0, 20:1. 10:1 and 7:1) to give the free base of the title compound.Use a method similar to the General Procedure 2-1 to give the titlecompound as a yellow solid (158 mg, 49%). MS (ES+) m/z: 434 (m+H)⁺;[α]²⁰ _(D) +18.7° (c 0.5, CH₃OH).

EXAMPLE 183(S)-(−)-7-Chloro-6-[4-(1-phenyl-ethylaminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the Example 182, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(250 mg, 0.59 mmol) and (S)-4-aminomethyl-N-(1-phenyl-ethyl)-benzamide(298 mg, 1.17 mmol) to give the title compound as a white solid (95 mg,29%). MS (ES+) m/z: 434 (M+H)⁺; [α]²⁰ _(D) −20.1° (c 0.5, CH₃OH).

EXAMPLE 1847-Chloro-6-{4-[(2-thiophen-2-yl-ethyl)-carbamoyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3, react7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(250 mg, 0.588 mmol) with4-aminomethyl-N-(2-thiophen-2-yl-ethyl)-benzamide (306 mg, 1.176 mmol)using palladium(II) acetate (26 mg, 0.118 mmol),tris(dibenzylideneacetone)dipalladium(0) (53 mg, 0.059 mmol), BINAP (220mg, 0.353 mmol) and cesium carbonate (383 mg, 1.176 mmol) in dioxane (6mL). Purify by chromatography on silica gel eluting with hexane/EtOAc(1:0, 7:3 and 1:1) to give7-chloro-6-{4-[(2-thiophen-2-yl-ethyl)-carbamoyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (233 mg, 91%). MS (ES+) m/z: 535 (M+H)⁺.

Use a method similar to the General Procedure 1-2, using7-chloro-6-{4-[(2-thiophen-2-yl-ethyl)-carbamoyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(223 mg, 0.416 mmol), to give7-chloro-6-{4-[(2-thiophen-2-yl-ethyl)-carbamoyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (145 mg, 79%) that was used without any further purification.

Use a method similar to the General Procedure 2-1, using7-chloro-6-{4-[(2-thiophen-2-yl-ethyl)-carbamoyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepine(145 mg, 0.330 mmol), to give the title compound as a solid (123 mg,67%). MS (ES+) m/z: 440 (M+H)⁺.

Examples 185-194 may be prepared essentially as described in Example 184by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

MS Yield (ES+) Ex. NH—R Compound (%) m/z 185

7-Chloro-6-{4-[(thiophen-2-ylmethyl)-carbamoyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate46 426(M + H)⁺ 186

7-Chloro-6-{4-[(pyridin-2-ylmethyl)-carbamoyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate49 421(M + H)⁺ 187

7-Chloro-6-{4-[(3-trifluoromethyl-pyridin-2-ylmethyl)-carbamoyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 39 489(M + H)⁺ 188

7-Chloro-6-{4-[(4-trifluoromethyl-pyridin-2-ylmethyl)-carbamoyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 26 489(M + H)⁺ 189

7-Chloro-6-{4-[(5-trifluoromethyl-pyridin-2-ylmethyl)-carbamoyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 29 489(M + H)⁺ 190

7-Chloro-6-{4-[(3-fluoro-pyridin-2-ylmethyl)-carbamoyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate37 439(M + H)⁺ 191

7-Chloro-6-{4-[(5-fluoro-pyridin-2-ylmethyl)-carbamoyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate51 439(M + H)⁺ 192

7-Chloro-6-{4-[(6-fluoro-pyridin-2-ylmethyl)-carbamoyl]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate54 439(M + H)⁺ 193

7-Chloro-6-[4-(2-pyridin-3-yl-ethylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate46 435(M + H)⁺ 194

7-Chloro-6-[4-(2-pyridin-4-yl-ethylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate27 435(M + H)⁺

EXAMPLE 1957-Chloro-6-[4-(2-pyridin-2-yl-ethylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 5-3 to react7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.471 mmol) and4-aminomethyl-N-(2-pyridin-2-yl-ethyl)-benzamide (241 mg, 0.942 mmol)using palladium(II) acetate (21 mg, 0.094 mmol),tris(dibenzylideneacetone)dipalladium(0) (43 mg, 0.047 mmol), BINAP (176mg, 0.283 mmol) and cesium carbonate (307 mg, 0.942 mmol) in dioxane (5mL). Purify by chromatography on silica gel eluting with hexane andhexane/EtOAc/DCM/methanol (7:1:1:1) to give7-chloro-6-[4-(2-pyridin-2-yl-ethylcarbamoyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (107 mg, 43%). MS (ES+) m/z: 531 (+H)⁺.

Use a method similar to the General Procedure 1-2, using7-chloro-6-[4-(2-pyridin-2-yl-ethylcarbamoyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(107 mg, 0.202 mmol), to give7-chloro-6-[4-(2-pyridin-2-yl-ethylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (85 mg, 97%) that was used without any further purification.

Use a method similar to the General Procedure 2-2, using7-chloro-6-[4-(2-pyridin-2-yl-ethylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(85 mg, 0.195 mmol), to give the title compound as a solid (103 mg,97%). MS (ES+) m/z: 435 (M+H)⁺.

EXAMPLE 1967-Chloro-6-[4-(piperidine-1-carbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Using a method similar to the General Procedure 5-2, react7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(500 mg, 1.17 mmol) with 4-(piperidin-1-ylcarbonyl)-benzylamine (308 mg,1.41 mmol). Purify by chromatography on silica gel eluting withhexane/EtOAc (20:1, 10:1, 7:1 and 5:1) to give7-chloro-6-[4-(piperidine-1-carbonyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil.

Use a method similar to the General Procedure 1-3 and purify bychromatography on silica gel eluting with DCM/2M ammonia in methanol(1:0, 20:1. 10:1 and 7:1) to give the free base of the title compound.Use a method similar to the General Procedure 2-1 to give the titlecompound as a yellow solid (284 mg, 47%). MS (ES+) m/z: 398 (M+H)⁺.

EXAMPLE 1977-Chloro-6-[2-(cyclohexylaminocarbonyl-pyridin-5-ylmethyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(348 mg, 0.82 mmol) with 5-aminomethyl-pyridine-2-carboxylic acidcyclohexylamide (200 mg, 0.86 mmol). Purify by chromatography on silicagel eluting with hexane/EtOAc (20:1, 10:1, 7:1 and 5:1) to give7-chloro-6-[2-(cyclohexylaminocarbonyl-pyridin-5-ylmethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas oil.

Use a method similar to the General Procedure 1-3 and purify bychromatography on silica gel eluting with DCM/2M ammonia in methanol(1:0, 20:1. 10:1 and 7:1) to give the free base of the title compound.

Use a method similar to the General Procedure 2-1 to give the titlecompound as a yellow solid (147 mg, 34%). MS (ES+) m/z: 413 (M+H)⁺.

EXAMPLE 198 7-Chloro-6-[2-(4-fluoro-baminocarbonyl)-pyridin-5-ylmethyl]-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

The title compound may be prepared essentially as described in Example197, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 5-aminomethyl-pyridine-2-carboxylic acid 4-fluoro-benzylamide (28%yield, MS (ES+) m/z 439).

EXAMPLE 1997-Chloro-6-(4-tert-butylthiocarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Combine6-(4-tert-butylcarbamoyl-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo-[d]azepine(0.3 g, 0.67 mmol),2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(Lawesson's reagent) (0.3, g, 0.67 mmol) and anhydrous 1,4-dioxane (10mL) in a sealed tube and heat at 100° C. for 5 h. Cool the reactionmixture to ambient temperature, evaporate the solvent and purify theresidue by SCX

EXAMPLE 200(S)-(−)-7-Chloro-6-[1-(4-fluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(7.0 g, 16.4 mmol) with (S)-1-(4-fluorophenyl)ethylamine (6.9 g, 49.3mmol) in toluene (175 mL). Purify by chromatography on silica geleluting with hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography[pre-wash column with methanol followed by DCM, load material dissolvedin DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentratein vacuo] to give7-chloro-6-[1-(S)-(4-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(3.96 g, 58%). GC-MS m/z: 414 (M>).

Use a method similar to the General Procedure 1-3 to deprotect7-chloro-6-[1-(S)-(4-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(3.92 g, 9.5 mmol) and purify by chromatography on silica gel elutingwith DCM/2M ammonia in methanol (99:1 to 80:20) to give the free base ofthe title compound. Use a method similar to the General Procedure 2-1and crystallize the solid from ethanol and methyl-t-butyl ether. Filterand dry the solid in a vacuum oven at 60° C. overnight to obtain thetitle compound (3.4 g, 83%). MS (ES+) m/z: 319 (M+H)⁺; [α]²⁰ _(D)−102.8° (c 0.5, MeOH).

Examples 201-209 may be prepared essentially as described in Example 200by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. The yields for the Step 1 (General Procedure5-2), optical rotation and MS (ES+) data are shown in the Table below.

Yield [α]²⁰ _(D) Ex. R Compound (%) (c, solvent) MS 201 4-F(R)-(+)-7-Chloro-6-[1-(4- 69 +89.2° 319 fluorophenyl)-ethylamino]- (c0.5, MeOH) (M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate 2022-F (+)-7-Chloro-6-[1-(2- 62 +105° 319 fluorophenyl)-ethylamino]- (c0.5, MeOH) (M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate 2034-CN (+)-7-Chloro-6-[1-(4- 60 +142.1° 326 cyanophenyl)-ethylamino]- (c0.5, MeOH) (M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate 2044-CN (−)-7-Chloro-6-[1-(4- 52 −149.3° 326 cyanophenyl)-ethylamino]- (c0.5, MeOH) (M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate 2052,3-diF (+)-7-Chloro-6-[1-(2,3- 14 +99.3° 337difluorophenyl)-ethylamino]- (c 0.5, MeOH) (M + H)⁺2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate 206 2,3-diF(−)-7-Chloro-6-[1-(2,3- 80 −107.9° 337 difluorophenyl)-ethylamino]- (c0.5, MeOH) (M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate 2072,4-diF (+)-7-Chloro-6-[1-(2,4- 94 +101.4° 337difluorophenyl)-ethylamino]- (c 0.5, MeOH) (M + H)⁺2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate 208 2,4-diF(−)-7-Chloro-6-[1-(2,4- 96 −107.9° 337 difluorophenyl)-ethylamino]- (c0.5, MeOH) (M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate 2093,5- (−)-7-Chloro-6-[1-(3,5-bis- 99 −93° 437 diCF₃trifluoromethyl-phenyl)- (c 0.5, MeOH) (M + H)⁺ ethylamino]-2,3,4,5-tetrahydro-1H-benzo [d]azepine Succinate

EXAMPLE 210(+)-7-Chloro-6-[(2-trifluoromethoxy-phenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineOxalate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.15 g, 0.35 mmol) with 1-(2-trifluoromethoxyphenyl)-ethylamine Isomer2 at 90° C. for 15 h. Use a method similar to the General Procedure 1-2and purify by reverse phase preparative HPLC to give the free base ofthe title compound. Use a method similar to the General Procedure 2-5 togive the title compound (27 mg, 16%). HPLC t_(R)=4.2 min (Chiralpak AD4.6×150 mm, 3 micron column, 1.0 mL/min of 94.8/5/0.2heptane/ethanol/dimethylethylamine isocratic; detector is at 225 nm);HRMS calcd for C₁₉H₂₀ClF₃N₂O 385.1294, found 385.1285; [α]²⁰ _(D) +95.4°(c 0.5, MeOH).

EXAMPLE 211(±)-7-Chloro-6-[1-(3-fluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Add palladium(II) acetate (27 mg, 0.12 mmol), BINAP (146 mg, 0.24 mmol),cesium carbonate (270 mg, 0.8 mmol) and(±)-1-(3-fluorophenyl)-ethylamine (230 mg, 1.6 mmol) to a solution of7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(250 mg, 0.6 mmol) in toluene (9 mL). Degas the slurry and fill withnitrogen. Heat the mixture to 95° C. for 16 h. Add additionalpalladium(II) acetate (0.1 equiv.) and BINAP (0.2 equiv.) and continueheating the reaction for an additional 24 h. Cool the mixture, dilutewith EtOAc (50 mL) then filter through Celite®. Concentrate the filtrateand purify by chromatography on silica gel eluting with hexane/EtOAc(9:1 to 1:1) followed by SCX chromatography to obtain(±)-7-chloro-6-[1-(3-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(138 mg, 56%). GC-MS m/z: 414 (M⁺).

Use a method similar to the General Procedure 1-3 to deprotect(±)-7-chloro-6-[1-(3-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(132 mg, 0.3 mmol) and purify by chromatography on silica gel elutingwith DCM/2M ammonia in methanol (99:1 to 90:10) to give the free base ofthe title compound. Use a method similar to the General Procedure 2-1 togive the title compound (98 mg, 70%). MS (ES+) m/z: 319 (M+H)⁺.

EXAMPLE 212(+)-7-Chloro-6-[1-(3-fluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Separate the two enantiomers of(±)-7-chloro-6-[1-(3-fluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate by normal phase chromatography (Chiralpak AD 2×25 cm, elutewith 95:5 heptane/isopropanol with 0.2% DMEA).

Use a method similar to the General Procedure 2-1 to obtain the titlecompound [23 mg, 30% recovery, 99% ee (Chiralpak AD, 4.6×250 mm, eluent:95:5 heptane/isopropanol, with 0.2% DMEA, 1.0 mL/min)]. MS (ES+) m/z:319 (M+H)⁺; [α]²⁰ _(D) +64° (c 0.5, MeOH).

EXAMPLE 213(−)-7-Chloro-6-[1-(3-fluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Add tris(dibenzylideneacetone)dipalladium(0) (3.4 g, 3.8 mmol), BINAP(4.7 g, 7.5 mmol), cesium carbonate (8.6 g, 26.3 mmol) and1-(3-fluorophenyl)-ethylamine Isomer 2 (5.8 g, 41.3 mmol) to a solutionof7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(8.0 g, 18.8 mmol) in toluene (225 mL). Degas the slurry and fill withnitrogen. Heat the mixture to 95° C. for 8 h. Add additionaltris(dibenzylideneacetone)dipalladium(0) (0.1 equiv.), and BINAP (0.2equiv.). Continue heating the reaction for an additional 16 h. Cool themixture, dilute with EtOAc (200 mL) then filter thru Celite®.Concentrate in vacuo and purify by chromatography on silica gel elutingwith hexane/EtOAc (9:1) followed by SCX chromatography to obtain7-chloro-6-[1-(3-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(6.0 g, 78%). GC-MS m/z: 414 (M⁺).

Use a method similar to the General Procedure 1-3 to deprotect7-chloro-6-[1-(3-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(6.0 g, 14.4 mmol). Purify by chromatography on silica gel eluting withDCM/2M ammonia in methanol (99:1 to 90:10) to give the free base of thetitle compound. Use a method similar to the General Procedure 2-1 andcrystallize the solid from ethanol and methyl-t-butyl ether. Filter anddry the solid under vacuum at 60° C. overnight to obtain the titlecompound [5.3 g, 84% yield, 99% ee (Chiralpak AD, 4.6×250 mm, eluent:95:5 heptane/EtOH, with 0.2% DMEA, 1.0 mL/min)]. MS (ES+) m/z: 319(M+H)⁺; [α]²⁰ _(D) −90.6° (c 0.5, MeOH).

EXAMPLE 214(±)-7-Chloro-6-[1-(2-fluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(250 mg, 0.6 mmol) with (±)-1-(2-fluorophenyl)-ethylamine (206 mg, 1.5mmol) in toluene (5 mL). Purify the residue by chromatography on silicagel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCXchromatography [pre-wash column with methanol followed by DCM, loadmaterial dissolved in DCM, then elute with DCM/2M ammonia in methanol(1:1) and concentrate in vacuo] to obtain(±)-7-chloro-6-[1-(2-fluorophenyl)ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(86 mg, 35%). GC-MS m/z: 414 (M⁺).

Use a method similar to the General Procedure 1-3 to deprotect(±)-7-chloro-6-[1-(2-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(85 mg, 0.2 mmol) and purify by chromatography on silica gel elutingwith DCM/2M ammonia in methanol (99:1 to 90:10) to give the free base ofthe title compound. Use a method similar to the General Procedure 2-1 togive the title compound (70 mg, 80%). MS (ES+) m/z: 319 (M+H)⁺.

Examples 215-216 may be prepared essentially as described in Example 214by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. The yields for the Step 1 (General Procedure5-1), optical rotation and MS (ES+) data are shown in the Table below.

MS Yield [α]²⁰ _(D) (ES+) Ex. R Compound (%) (c, solvent) m/z 215 3-CN(+)-7-Chloro-6-[1-(3- 58 +100.7° 326 cyanophenyl)-ethylamino]- (c 0.5,MeOH) (M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate 216 3-CN(−)-7-Chloro-6-[1-(3- 90 −109.7° 326 cyanophenyl)-ethylamino]- (c 0.5,MeOH) (M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate

EXAMPLE 217(S)-(−)-7-Chloro-6-(1-phenyl-ethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Add palladium(II) acetate (396 mg, 1.8 mmol), BINAP (2.2 g, 3.5 mmol),cesium carbonate (8.0 g, 24.6 mmol), and IS-(−)methylbenzylamine (6.4 g,52.9 mmol) to a solution of7-chloro-6-trifluoromethanesulfonyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(7.5 g, 17.6 mmol) in toluene (173 ml). Degas the slurry and fill withnitrogen. Heat the mixture to 95° C. for 16 h. GC/MS shows some staringmaterial still present after 16 h, so add additional palladium(II)acetate (0.1 equiv.), BINAP, and IS-(−)-methylbenzylamine (1.0 equiv.).Continue heating the reaction for an additional 24 h. Cool the mixture,dilute with EtOAc (250 ml) then filter through Celite®. Concentrate invacuo and purify by chromatography on silica gel eluting withhexane/EtOAc/methanol (84:15:1) followed by SCX chromatography to give(S)-7-chloro-6-(1-phenyl-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(4.38 g, 63%). GC-MS m/z: 396 (M⁺).

Use a method similar to the General Procedure 1-1 to deprotect(S)-7-chloro-6-(1-phenyl-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(4.3 g, 10.8 mmol). Purify by chromatography on silica gel eluting withDCM/2M ammonia in methanol (99/1 to 80/20) to give the free base of thetitle compound. Use a method similar to the General Procedure 2-1 andcrystallize the solid from ethanol and methyl-t-butyl ether. Filter anddry the solid in a vacuum oven at 70° C. overnight to obtain the titlecompound (3.6 g, 80%). MS (ES+) m/z: 301 (M+H)⁺. [c]²⁰ _(D) −95.6° (c0.5, MeOH).

Examples 218-227 may be prepared essentially as described in Example 217by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. The yields for the Step 1, optical rotationor enantiomeric excess (determined by chiral HPLC) and MS (ES+) data areshown in the Table below.

[α]²⁰ _(D) MS Yield (c, solvent) (ES+) Ex. R Compound (%) or ee (%) m/z218 H (R)-(+)-7-Chloro-6-(1-phenyl- 47 +100.5° 301ethylamino)-2,3,4,5-tetrahydro- (c 0.5, MeOH) (M + H)⁺1H-benzo[d]azepine Succinate 219 4-CF₃ (+)-7-Chloro-6-[1-(4- 55 +95.7°369 trifluoromethyl-phenyl)- (c 0.5, MeOH) (M + H)⁺ethylamino]-2,3,4,5-tetrahydro- 1H-benzo[d]azepine Succinate 220 3-CF₃7-Chloro-6-[1-(3- 90 95% 369 trifluoromethyl-phenyl)- ee (M + H)⁺ethylamino]-2,3,4,5-tetrahydro- 1H-benzo[d]azepine Succinate, Isomer 1221 3,4-diF 7-Chloro-6-[1-(3,4- 28 94% 337 trifluorophenyl)-ethylamino]-ee (M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate, Isomer 1222 3,4-diF (+)-7-Chloro-6-[1-(3,4- 81 +89.0° 337trifluorophenyl)-ethylamino]- (c 0.5, MeOH) (M + H)⁺2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate 223 3,4,5-7-Chloro-6-[1-(3,4,5- 40 ND 355 triF trifluorophenyl)-ethylamino]- (M +H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate, Isomer 2 2243-OCH₃ 7-Chloro-6-[1-(3-methoxy- 53 ND 331 phenyl)-ethylamino]-2,3,4,5-(M + H)⁺ tetrahydro-1H-benzo[d]azepine Hydrochloride, Isomer 1 2254-OCH₃ 7-Chloro-6-[1-(4-methoxy- 53 >99% 331phenyl)-ethylamino]-2,3,4,5- ee (M + H)⁺ tetrahydro-1H-benzo[d]azepineHydrochloride, Isomer 1 226 4-OPh 7-Chloro-6-[1-(4- 27 ND 393phenoxyphenyl)-ethylamino]- (M + H)⁺ 2,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate, Isomer 1 227 4-OPh 7-Chloro-6-[1-(4- 27 ND393 phenoxyphenyl)-ethylamino]- (M + H)⁺ 2,3,4,5-tetrahydro-1H-benzo[d]azepine Succinate, Isomer 2 ND = Not determined

EXAMPLE 228(−)-7-Chloro-6-[1-(3-chloro-4-fluoro-phenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(426 mg, 1.0 mmol) with 1-(3-chloro-4-fluoro-phenyl)-ethylamine Isomer 1(226 mg, 1.3 mmol). Purify by chromatography on silica gel eluting withEtOAc/hexane (1:7) to give7-chloro-6-[1-(3-chloro-4-fluoro-phenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (293 mg, 65%).

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-[1-(3-chloro-4-fluoro-phenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1 (293 mg, 0.65 mmol). Purify by chromatography on silica geleluting with DCM/2M ammonia in methanol (94:6) to give the free base ofthe title compound as an oil (157 mg, 68%). MS (ES+)-m/z: 353 (M+H)⁺.Use a method similar to preparation E-1 to convert the free base to thetitle compound. [α]²⁰ _(D) −115.9° (c 0.5, MeOH).

Examples 229-235 may be prepared essentially as described in Example 228by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. The yields for the Step 1 (General Procedure5-3), optical rotation and MS (ES+) data are shown in the Table below.

Yield [α]²⁰ _(D) Ex. R Compound (%) (c, solvent) MS 229 3-Cl(+)-7-Chloro-6-[1-(3- 17 +119.6° 335 chlorophenyl)-ethylamino]- (c 0.5,CH₃OH) (M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate 2302-Cl (+)-7-Chloro-6-[1-(2- 30 +45.0° 335 chlorophenyl)-ethylamino]- (c0.5, CH₃OH) (M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate231 4-CH₃ (R)-(+)-7-Chloro-6-(1-p- 57 +107° 315tolylethylamino)-2,3,4,5-tetrahydro- (c 0.5, MeOH) (M + H)⁺1H-benzo[d]azepine Succinate 232 4-CH₃ (S)-(−)-7-Chloro-6-(1-p- 54−97.2° 315 tolylethylamino)-2,3,4,5-tetrahydro- (c 0.5, MeOH) (M + H)⁺1H-benzo[d]azepine Succinate 233 3-Cl, (+)-7-Chloro-6-[1-(3-chloro-4- 84+115.0° 353 4-F fluorophenyl)-ethylamino]-2,3,4,5- (c 0.5, CH₃OH) (M +H)⁺ tetrahydro-1H-benzo[d]azepine Succinate 234 3,5-diF(−)-7-Chloro-6-[1-(3,5- 50 −97.6° 337 dilfuorophenyl)-ethylamino]- (c0.5, MeOH) (M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate 2353,5-diF (+)-7-Chloro-6-[1-(3,5- 41 +91.0° 337difluorophenyl)-ethylamino]- (c 0.5, MeOH) (M + H)⁺2,3,4,5-tetrahydro-1H- benzo[d]azepine Succinate

EXAMPLE 236(d)-7-Chloro-6-[1-(4-chlorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(852 mg, 2.0 mmol) and (±)-4-chloro-(α-methyl)benzylamine (622 mg, 4.0mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc(1:0 and 9:1) to obtain(−)-7-chloro-6-[1-(4-chlorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(326 mg, 38%). MS (ES+) m/z: 431 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect(±)-7-chloro-6-[1-(4-chlorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by chromatography on silica gel eluting with DCM/2M ammonia inmethanol (95:5) to give the free base of the title compound (61 mg,100%). MS (ES+) m/z: 335 (M+H)⁺. Use a method similar to the GeneralProcedure 2-1 to obtain the title compound.

EXAMPLES 237 AND 238(−)-7-Chloro-6-[1-(4-chlorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate and(+)-7-Chloro-6-[1-(4-chlorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Submit(−)-7-chloro-6-[1-(4-chlorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(326 mg, 0.76 mmol) to chiral chromatography (Chiralpak AD, 4.6×150 mm,eluting with heptane/ethanol (9:1) with 0.2% DMEA, 1 mL/min) to providethe two enantiomers:7-chloro-6-[1-(4-chlorophenyl)ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1 (102 mg, t_(R)=5.25 min) and7-chloro-6-[1-(4-chlorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 2 (110 mg, t_(R)=6.40 min).

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-[1-(4-chlorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1. Purify by chromatography on silica gel eluting with DCM/2Mammonia in methanol (95:5) to give7-chloro-6-[1-(4-chlorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1 (Example 237, 82 mg, 100%). MS (ES+) m/z: 335 (M+H)⁺. Use amethod similar to the General Procedure 2-1 to obtain the titlecompound. [α]²⁰ _(D) −127.7° (c 0.5, CH₃OH).

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-[1-(4-chlorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 2. Purify by chromatography on silica gel eluting with DCM/2Mammonia in methanol (95:5) to give7-chloro-6-[1-(4-chlorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 2 (Example 238, 68 mg, 78%). MS (ES+) m/z: 335 (M+H)⁺. Use amethod similar to the General Procedure 2-1 to obtain the titlecompound. [α]²⁰ _(D) +133.6° (c 0.5, CH₃OH).

EXAMPLES 239 AND 2407-Chloro-6-[1-(2,5-difluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate Isomer 1, and7-chloro-6-[1-(2,5-difluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate Isomer 2

Use a method similar to the General Procedure 5-1 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(550 mg, 1.27 mmol) and crude (±)-α-methyl-(2′,5′-difluoro)benzylamine(400 mg).

Separate the two enantiomers by chiral chromatography (eluent: 75:20:5heptane/isopropanol/methanol, 4.6×250 mm Chiralpak AD, 1 mL/min, uv 260nm) to obtain7-chloro-6-[1-(2,5-difluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1 [150 mg, 29%; chiral HPLC: t_(R)=4.5 min; MS (ES+) m/z: 433(M+H)⁺] and7-chloro-6-[1-(2,5-difluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 2 [130 mg, 25%; chiral HPLC: t_(R)=5.5 min; MS (ES+) m/z: 433(M+H)⁺], both as opaque oils which solidify upon standing to off-whitewaxy solids.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-[1-(2,5-difluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1 (140 mg, 0.32 mmol). Purify by SCX chromatography to give7-chloro-6-[1-(2,5-difluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1 (102 mg, 95%) as a yellow oil. Use a method similar to theGeneral Procedure 2-1 to obtain the Isomer 1 of the title compound (130mg, 95%) as an off-white solid. MS (ES+) m/z: 337 (+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-[1-(2,5-difluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 2 (125 mg, 0.29 mmol). Purify by SCX chromatography to give7-chloro-6-[1-(2,5-difluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 2 (87.7 mg, 90%) as a yellow oil. Use a method similar to theGeneral Procedure 2-1 to obtain the Isomer 2 of the title compound (117mg, 99%) as an off-white solid. MS (ES+) m/z: 337 (M+H)⁺.

EXAMPLE 241(−)-7-Chloro-6-[1-(3,5-difluoro-4-methoxy-phenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(300 mg, 0.7 mmol) and crudeα-methyl-(3′,5′-difluoro-4′-methoxy)benzylamine (380 mg). Purify bychromatography on silica gel eluting with hexane/EtOAc (95:5) followedby chiral chromatography [heptane/isopropanol/dimethylethylamine(90:10:0.2), 4.6×250 mm Chiralpak AD, 1 mL/min, uv 250 nm] to give7-chloro-6-[1-(3,5-difluoro-4-methoxy-phenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1 [59 mg, 18% yield, 99% ee, chiral HPLC: t_(R)=6.0 min; MS (ES−)m/z: 461 (M−H)⁻] and7-chloro-6-[1-(3,5-difluoro-4-methoxy-phenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 2 [50 mg, 15% yield, 99% ee, chiral HPLC: t_(R)=7.7 min; MS (ES−)m/z: 461 (M−H)⁻]. Use a method similar to the General Procedure 1-1 todeprotect7-chloro-6-[1-(3,5-difluoro-4-methoxy-phenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 2 (50 mg, 0.14 mmol). Purify by SCX chromatography to give7-chloro-6-[1-(3,5-difluoro-4-methoxy-phenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 2 (35 mg, 70%) as a yellow oil. Use a method similar to theGeneral Procedure 2-1, using7-chloro-6-[1-(3,5-difluoro-4-methoxy-phenyl)ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 2 (35 mg, 0.10 mmol), to give the title compound (44 mg, 97%) asan off-white powder. MS (ES+) m/z: 367 (+H)⁺; [α]²⁰ _(D) −107.0° (c 0.5,CH₃OH).

EXAMPLE 242(+)-7-Chloro-6-[(2-methylphenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineOxalate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.15 g, 0.35 mmol) with (R)-1-(2-methyl)-ethylamine (162 mg, 1.2 mmol)at 90° C. for 17 h. Deprotect according to the General Procedure 1-2.Purify by reverse phase preparative HPLC and form the oxalate saltaccording to the General Procedure 2-5 to give the title compound (72mg, 51%). HPLC t_(R)=4.0 min (Chiralpak AD 4.6×150 mm, 3 micron column,1.0 mL/min of 89.8:10:0.2 heptane/isopropanol/DMEA, isocratic; detectoris at 225 nm); HRMS calcd for C₁₉H₂₃ClN₂ 315.1628, found 315.1623. [α]²⁰_(D) +67.2° (c 0.5, CH₃OH).

EXAMPLE 243(+)-7-Chloro-6-(indan-1-ylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.5 mmol) with (R)-1-aminoindan (188 mg, 1.4 mmol) in toluene(5 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc(9:1 to 1:1) followed by SCX chromatography [pre-wash column withmethanol followed by DCM, load material dissolved in DCM, then elutewith DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to give7-chloro-6-(indan-1-ylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(129 mg, 67%). GC-MS m/z: 408 (M⁺).

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-(indan-1-ylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(125 mg, 0.3 mmol) and purify by chromatography on silica gel elutingwith DCM/2M ammonia in methanol (99:1 to 80:20) to give the free base ofthe title compound. Use a method similar to the General Procedure 2-1 togive the title compound (104 mg, 78%). MS (ES+) m/z: 313 (M+H)⁺. [α]²⁰_(D) +73.9° (c 0.5, MeOH).

EXAMPLE 244(+)-7-Chloro-6-(5-fluoro-indan-1-ylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(210 mg, 0.5 mmol) with 5-fluoro-indan-ylamine Isomer 1 (161 mg, 1.1mmol) in toluene (10 mL). Purify by chromatography on silica gel elutingwith hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography to obtain7-chloro-6-[1-(3,5-bis-trifluoromethyl-phenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1 (616 mg, 99%).

Use a method similar to the General Procedure 1-3 to deprotect7-chloro-6-(5-fluoro-indan-ylamine)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1 (200 mg, 0.5 mmol). Purify by chromatography on silica geleluting with DCM/2M ammonia in methanol (99/1 to 90/10) to give the freebase of the title compound. Use Preparation E-1 to give the titlecompound (140 mg, 66%). MS (ES+) m/z: 331 (M+H)⁺. [α]²⁰ _(D) +80.0° (C,0.5, MeOH)

EXAMPLE 245(±)-7-Chloro-6-(2,3-dihydro-benzofuran-3-ylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.15 g, 0.35 mmol) with 2,3-dihydro-benzofuran-3-ylamine (prepared asdescribed in WO 0069816) (0.14 g, 1.1 mmol) at 90° C. for 18 h.

Use a method similar to the General Procedure 1-2 and purify by reversephase preparative HPLC [Zorbax SB-Phenyl 4.6×150 mm, 5 micron column, 1mL/min of 0.1% TFA in water/ACN (9:1 to 1:9) over 30 min, detector at230 and 254 nm n].

Use a method similar to the General Procedure 2-1 to give the titlecompound (4.3 mg, 3%). HRMS calcd for C₁₈H₁₉ClN₂O 315.1264, found315.1256.

EXAMPLE 2467-Chloro-6-(indan-2-yl-amino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(426 mg, 1.0 mmol) and 2-aminoindane (400 mg, 3.0 mmol), to give7-chloro-6-(indan-2-yl-amino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a slightly yellow oil (354 mg, 86%). MS (ES+) m/z: 409 (M+H)⁺.

Using a method similar to the General Procedure 1-1, deprotect7-chloro-6-(indan-2-yl-amino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(354 mg, 0.87 mmol) to obtain7-chloro-6-(indan-2-yl-amino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as apale-yellow oil (166 mg, 61%). MS (ES+) m/z: 313 (M+H)⁺. Use a methodsimilar to the General Procedure 2-1 to give the title compound.

EXAMPLE 247(−)-7-Chloro-6-[(N-methyl)-1-phenylethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Dissolve(−)-7-chloro-6-(1-phenyl-ethylamine)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(192 mg) in DCE (5 mL) and add acetic acid (0.33 mL, 5.8 mmol),formaldehyde (37% solution; 0.5 mL) and sodium triacetoxyborohydride(570 mg, 2.7 mol) and stir the reaction at ambient temperature for 16 h.Dilute the reaction with DCM and wash with 1N aqueous NaOH. Dry theorganic layers over Na₂SO₄, filter and concentrate. Purify bychromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1 and5:1) to give(−)-7-chloro-6-(methyl-1-phenylethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil.

Use a method similar to the General Procedure 1-3 to deprotect(−)-7-chloro-6-(methyl-1-phenylethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand purify by SCX chromatography to give the free base of the titlecompound. Use a method similar to the General Procedure 2-1 to give thetitle compound as a white solid (176 mg, 85%). MS (ES+) m/z: 315 (M+H)⁺.[α]²⁰ _(D) −5.4° (c 0.5, CH₃OH).

EXAMPLE 2487-Chloro-6-[(N-methyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Dissolve 6-benzylamino-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(330 mg, 0.86 mmol) in DCM (3 mL) and add triethylamine (250 □L, 1.8mmol) followed by di-tert-butyl-dicarbonate (260 mg, 1.2 mmol). Stir atambient temperature for 1 h. Pour the mixture into water (250 mL),extract with DCM (3×25 mL) and concentrate in vacuo to give, afterchromatography on silica gel eluting with hexane/EtOAc (9:1),6-benzylamino-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil (260 mg, 78%).

Dissolve6-benzylamino-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(50 mg, 0.11 mmol) in acetonitrile (3 mL) and add a solution offormaldehyde in water (37%, 85 μL, 0.97 mmol) followed by sodiumcyanoborohydride (16.5 mg, 0.26 mmol). Heat the solution to reflux 1 h,cool to ambient temperature, add glacial acetic acid (0.25 mL) and stir72 h. Pour the mixture into water (100 mL) containing methanol (1 mL),extract with DCM (3×20 mL), wash the organic extracts with brine, dryover MgSO₄, filter and concentrate in vacuo. Dissolve the resultingresidue in DCM (5 mL), and add trifluoroacetic acid (2 mL). Stir for 2 hat ambient temperature and evaporate the solvent. Purify by SCXchromatography. Use a method similar to the General Procedure 2-1 togive the title compound (45 mg, 95%). MS (ES+) m/z: 301 (M+H)⁺.

EXAMPLE 2497-Chloro-6-[(N-methyl)-3-fluorobenzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

The title compound may be prepared essentially as described in Example248 by using7-chloro-6-(3-fluorobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(85% yield and MS (ES+) an/z 319 (M+H)⁺).

EXAMPLE 2507-Chloro-6-(1-phenyl-cyclopropylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.2 g, 0.47 mmol) with 1-phenyl-cyclopropylamine (0.2 g, 1.41 mmol)using tris(dibenzylideneacetone)dipalladium(0) (43.0 mg, 0.05 mmol),BINAP (0.1 g, 0.15 mmol) and cesium carbonate (0.3 g, 0.97 mmol) at 90°C. for 17 h to obtain7-chloro-6-(1-phenyl-cyclopropylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil.

Use a method similar to the General Procedure 1-1 to obtain the freebase of the title compound as a yellow oil. Use a method similar to theGeneral Procedure 2-1 to obtain the title compound as a white solid (85mg, 33%).

Example 251 may be prepared essentially as described in Example 250 byusing7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 1-(2,4-dichlorophenyl)-cyclopropylamine. The overall yield (3 steps)is shown in the Table below.

Yield Ex. Structure Compound (%) 251

7-Chloro-6-[1-(2,4-dichlorophenyl)-cyclopropylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate19

EXAMPLE 252(±)-7-Chloro-6-(2,3-dihydro-benzofuran-3-yl-methylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple2,3-dihydro-benzofuran-3-yl-methylamine (prepared as described in WO0069816) (0.14 g, 1.1 mmol) with7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.15 g, 0.35 mmol) at 90° C. for 18 h.

Use a method similar to the General Procedure 1-2 to deprotect7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by reverse phase preparative HPLC [Zorbax SB-Phenyl 4.6×150 mm 5micron column, 1 mL/min of 1% TFA in water/ACN (9:1 to 1:9) over 30 min,detector at 230 and 254 nm]. Use a method similar to the GeneralProcedure 2-1 to give the title compound (4.3 mg, 3%).

EXAMPLE 2537-Chloro-6-[(2,3-dihydrobenzo[b]-5-yl)-methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Suspend commercially available 2,3-dihydrobenzo[b]furan-5-yl-methylaminehydrochloride (1.0 g, 5.4 mmol) in DCM (100 mL). Add 1N aqueous NaOH (15mL) and stir until all solids dissolve. Add two spatulas of NaCl. Stirthe mixture and extract twice with DCM. Combine the organic layers, dryover Na₂SO₄, and concentrate in vacuo to obtain2,3-dihydrobenzo[b]furan-5-yl-methylamine (650 mg, 81%). MS (ES+) m/z:133 (M+H—NH₃)⁺.

Use a method similar to the General Procedure 5-3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(426 mg, 1.0 mmol) with 5-aminomethyl-2,3-dihydrobenzo[b]furane (223 mg,1.5 mmol). Purify by chromatography on silica gel eluting withhexane/EtOAc (1:0 and 9:1) to obtain7-chloro-6-[(2,3-dihydrobenzo[b]furan-5-yl)-methylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(244 mg, 58%). MS (ES+) m/z: 425 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-[(2,3-dihydrobenzo[b]furan-5-yl)-methylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by chromatography on silica gel eluting with DCM/2M ammonia inmethanol (95:5) to give the free base of the title compound (105 mg,32%). MS (ES+) m/z: 329 (M+H)⁺. Use a method similar to the GeneralProcedure 2-1 to obtain the title compound.

Examples 254-260 may be prepared essentially as described in Example 253by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. The yields for the Step 1 (General Procedure5-3) and MS (ES+) data are shown in the Table below.

MS Yield (ES+) Ex. NH—R Compound (%) m/z 254

(±)-7-Chloro-6-[C-(3-methyl-2,3-dihydro-benzofuran-5-yl)-methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 50 343(M + H)⁺ 255

(±)-7-Chloro-6-[C-(3-methyl-2,3-dihydro-benzofuran-6-yl)-methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 66 343(M + H)⁺ 256

7-Chloro-6-[C-(3,3-dimethyl-2,3-dihydro-benzofuran-6-yl)-methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 57 357(M + H)⁺ 257

7-Chloro-6-[C-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 64 357(M + H)⁺ 258

7-Chloro-6-[C-(2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-5-yl)-methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 47 371(M + H)⁺ 259

7-Chloro-6-[C-(2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-6-yl)-methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 67 371(M + H)⁺ 260

7-Chloro-6-[(2,2-dimethyl-chroman-6-yl)-methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate24 371(M + H)⁺

EXAMPLE 2617-Chloro-6-(naphthalen-2-yl-methylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple2-aminomethylnaphthalene (prepared as described in WO 9509159) (0.17 g,1.1 mmol) with7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine-(0.15g, 0.35 mmol) at 90° C. for 18 h.

Use a method similar to the General Procedure 1-2 to give the free baseof the title compound. HRMS calcd for C₂₁H₂₁ClN₂ 337.1471, found337.1461. Use a method similar to the General Procedure 2-1 to give thetitle compound (104 mg, 66% overall).

EXAMPLE 2627-Chloro-6-[(quinolin-6-yl-methyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 5-2, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.2 g; 0.35 mmol) and 6-aminomethyl-quinoline (0.2 g, 1.06 mmol) withtris(dibenzylideneacetone)dipalladium(0) (32.0 mg, 0.04 mmol), BINAP(44.0 mg, 0.07 mmol) and cesium carbonate (0.2 g, 0.71 mmol) at 90° C.for 17 h, to obtain7-chloro-6-[(quinolin-6-yl-methyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil.

Use a method similar to the General Procedure 1-1 to obtain the freebase of the title compound as a yellow oil. Use a method similar to theGeneral Procedure 2-2 to form the hydrochloride salt and purify byreverse phase preparative HPLC [Zorbax SB-Phenyl 21.2×250 mm, 5 microncolumn, 22 mL/min of 0.1% HCl in water/acetonitrile (9:1 to 1:1) over 30min. detector at 230 nm) to obtain the title compound as a white solid(50 mg, 56% overall). MS (ES+) m/z: 338 (M+H)⁺.

Examples 263-266 may be prepared essentially as described in Example 262by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

MS Yield (ES+) Ex. NH—R Compound (%) m/z 263

7-Chloro-6-[(isoquinolin-3-yl-methyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride63 338(M + H)⁺ 264

7-Chloro-6-[(quinolin-3-yl-methyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride35 338(M + H)⁺ 265

7-Chloro-6-[(quinolin-2-yl-methyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride20 338(M + H)⁺ 266

7-Chloro-6-[(2-phenyl-benzoxazol-6-yl-methyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride15 404(M + H)⁺

EXAMPLE 2676-[(Benzofuran-6-ylmethyl)-amino]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.2 g, 0.35 mmol) and 6-aminomethyl-benzofuran (0.2 g, 1.06 mmol) withtris(dibenzylideneacetone)dipalladium (0) (32.0 mg, 0.04 mmol), BINAP(88.0 mg, 0.11 mmol) and cesium carbonate (0.2 g, 0.71 mmol) at 90° C.for 17 h, to obtain6[(benzofuran-6-yl-methyl)-amino]-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil.

Use a method similar to the General Procedure 1-1 to obtain the freebase of the title compound as a yellow oil. Use a method similar to theGeneral Procedure 2-1 to obtain the title compound as a white solid (72mg, 46% overall). MS (ES+) m/z: 327 (M+H)⁺.

Examples 268-271 may be prepared essentially as described in Example 267by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

MS Yield (ES+) Ex. NH—R Compound (%) m/z 268

6-[(Benzo[1,3]dioxol-4-yl-methyl)-amino]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 54 331(M + H)⁺ 269

6-[(Benzo[1,3]dioxol-5-yl-methyl)-amino]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 55 331(M + H)⁺ 270

6-(Benzo[b]thiophen-4-yl-methylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 73 343(M + H)⁺ 271

6-(Benzo[b]thiophen-6-yl-methylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 48 343(M + H)⁺

EXAMPLE 2726-[(Benzothiazol-6-yl-methyl)-amino]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineOxalate

Using a method similar to the General Procedure 5-4, combine6-amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.1 g, 0.35 mmol), 6-bromomethyl-benzothiazole (80 mg, 0.35 mmol), andpotassium carbonate (47.0 mg, 0.35 mmol) in anhydrous DMF (1 mL) in asealed tube. Heat at 150° C. for 3 h to obtain6-[(benzothiazol-6-yl-methyl)-amino]-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil.

Use a method similar to the General Procedure 1-1 to obtain the freebase of the title compound as a yellow oil. Use a method similar to theGeneral Procedure 2-5 to obtain the title compound as a white solid (25mg, 16% overall). MS (ES+) m/z: 344 (M+H)⁺.

EXAMPLE 2737-Chloro-6-[(quinolin-8-yl-methyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Using a method similar to the General Procedure 5-4, combine6-amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.1 g, 0.35 mmol), 8-bromomethyl-quinoline (83.6 mg, 0.038 mmol),cesium carbonate (0.2 g, 0.68 mmol) and anhydrous acetonitrile (1 mL) ina sealed tube and heat at 50° C. for 12 h to obtain7-chloro-6-[(quinolin-8-yl-methyl)-amino)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil.

Use a method similar to the General Procedure 1-1 to obtain the freebase of the title compound as a yellow oil. Use a method similar to theGeneral Procedure 2-2 to form the hydrochloride salt and purify byreverse phase preparative HPLC [Zorbax SB-Phenyl 21.2×250 mm, 5 microncolumn, 22 mL/min of 0.1% HCl in water/acetonitrile (9:1 to 1:1) over 30min, detector at 230 nm) to obtain the title compound as a white solid(13 mg, 8% overall). MS (ES+) m/z: 338 (M+H)⁺.

EXAMPLE 2747-Chloro-6-[(2-cyclohexyl-benzothiazol-6-yl-methyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Using a method similar to the General Procedure 5-4, combine6-amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(60 mg, 0.21 mmol), 6-bromomethyl-2-cyclohexyl-benzothiazole (0.1 g,0.31 mmol), potassium carbonate (58 mg, 0.42 mmol) and anhydrous toluene(2 mL) in a sealed tube and heat at 100° C. for 72 h to obtain7-chloro-6-[(2-cyclohexyl-benzothiazol-6-yl-methyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil.

Use a method similar to the General Procedure 1-1 to obtain the freebase of the title compound as a yellow oil. Use a method similar to theGeneral Procedure 2-1 to obtain the title compound as a white solid (40mg, 35% overall). MS (ES+) m/z: 427 (M+H)⁺.

Examples 275-277 may be prepared essentially as described in Example 274by using6-amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate bromide. Overall yields and MS (ES+) data are shownin the Table below.

Yield MS Ex. NH—R Compound (%) (ES+) m/z 275

7-Chloro-6-[(2-phenyl-benzothiazol-6-yl-methyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 39 420(M + H)⁺ 276

6-[(2-Benzyl-benzothiazol-6-yl-methyl)-amino]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 36 453(M + H)⁺ 277

6-[(Benzoxazol-6-yl-methyl)-amino]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 7 328(M + H)⁺

EXAMPLE 2787-Chloro-6-[(1-methyl-indol-4-yl-methyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Using a method similar to the General Procedure 5-1, couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetra-hydro-1H-benzo[d]azepine(0.1 g, 0.24 mmol) with 4-aminomethyl-1-methylindole (0.1 g, 0.71 mmol)to obtain7-chloro-6-[(1-methyl-indol-4-yl-methyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil.

Use a method similar to the General Procedure 1-1 to obtain the freebase of the title compound as a yellow oil. Use a method similar to theGeneral Procedure 2-1 to obtain the title compound as a white solid (0.1g, 91% overall). MS (ES+) m/z: 340 (M+H)⁺.

Examples 279-280 may be prepared essentially as described in Example 278by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith the appropriate amine. Overall yields and MS (ES+) data are shownin the Table below.

MS Ex. NH—R Compound (%) (ES+) m/z 279

7-Chloro-6-[(1-methyl-indol-6-yl-methyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 42 340(M + H)⁺ 280

6-[(Benzofuran-6-ylmethyl)-amino]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[djazepineSuccinate 46 327(M + H)⁺

EXAMPLE 2817-Chloro-6-(pyridin-2-ylmethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 5-1 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(500 mg, 1.17 mmol) with pyridin-2-ylmethylamine (254 mg, 2 equiv.)using palladium acetate (0.1 equiv.), BINAP (0.3 equiv.) and cesiumcarbonate (1.4 equiv.) in toluene (5 mL). Purify the residue bychromatography on silica gel eluting with hexane/EtOAc (10:1, 5:1, 3:1,and 1:1) to give7-chloro-6-(pyridin-2-ylmethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil.

Use a method similar to the General Procedure 1-3 to deprotect7-chloro-6-(pyridin-2-ylmethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by SCX chromatography followed by silica gel chromatographyeluting with DCM/2M ammonia in methanol (1:0, 40:1, 20:1 and 10:1) togive the free base of the title compound. Use a method similar to theGeneral Procedure 2-2 to give the title compound as an off white solid(207 mg, 55% overall). MS (ES+) m/z: 288 (M+H)⁺.

EXAMPLE 2827-Chloro-6-(pyridin-4-ylmethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

may be prepared essentially as described in Example 281 by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand pyridin-4-ylmethylamine (28% yield, and MS (ES+) 288 (M+H)⁺).

EXAMPLE 283(±)-7-Chloro-6-[(1-pyridin-4-yl-ethyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(400 mg, 0.94 mmol) and (±)-1-pyridin-4-yl-ethylamine (prepared asdescribed in Bull. Kor. Chem. Soc. 1998, 19 (8), 891-893) (172 mg, 1.41mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc(1:0, 4:1 and 1:1) to give(±)-7-chloro-6-[(1-pyridin-4-yl-ethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.

Use a method similar to the General Procedure 1-1 to give the free baseof the title compound (73 mg, 26%). Use a method similar to the GeneralProcedure 2-1, using(±)-7-chloro-6-[(1-pyridin-4-yl-ethyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(73 mg, 0.243 mmol), to give the title compound (31 mg, 31%). MS (ES+)m/z: 302 (M+H)⁺.

Examples 284-287 may be prepared essentially as described in Example 283by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. The yields for the Step 1 (General Procedure5-3) and MS (ES+) data are shown in the Table below.

Yield MS Ex. NH—R Compound (%) (ES+) m/z 284

7-Chloro-6-(5-fluoro-pyridin-3-ylmethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate88 306(M + H)⁺ 285

7-Chloro-6-(6-trifluoromethyl-pyridin-3-yl-methylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate83 356(M + H)⁺ 286

7-Chloro-6-(4-trifluoromethyl-pyridin-3-yl-methylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate60 356(M + H)⁺ 287

7-Chloro-6-[(6-trifluoromethyl-pyridin-2-ylmethyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate84 356(M + H)⁺

EXAMPLE 2887-Chloro-6-[(5-fluoro-pyridin-2-ylmethyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1 to couple2-aminomethyl-5-fluoro-pyridine (230 mg, 1.8 mmol) and a solution of7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(500 mg, 1.2 mmol) in toluene (4 mL). Purify by chromatography on silicagel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCXchromatography to give7-chloro-6-[(5-fluoro-pyridin-2-ylmethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(302 mg, 64%). GC-MS m/z: 402 (M⁺).

Dissolve7-chloro-6-[(5-fluoro-pyridin-2-ylmethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(297 mg, 0.74 mmol) in ethanol (5 mL). Add 5N aqueous NaOH (10 equiv.)and stir for 1 h at ambient temperature. Concentrate in vacuo and purifyby SCX chromatography followed by chromatography on silica gel elutingwith DCM/2M ammonia in methanol (99:1 to 9:1) to obtain the free base ofthe title compound. Use a method similar to the General Procedure 2-1and crystallize the solid from methanol and diethyl ether. Dry the solidin a vacuum oven at 60° C. overnight to obtain the title compound (181mg, 58%). MS (ES+) m/z: 306 (M+H)⁺.

EXAMPLE 2897-Chloro-6-{[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethyl]-amino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-6-trifluoromethanesulfonyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(370 mg, 0.9 mmol) with 2-aminomethyl-5-(2,2,2-trifluoroethoxy)-pyridine(180 mg, 0.9 mmol) in toluene (8 mL). Purify by chromatography on silicagel eluting with hexane/EtOAc (10:1, 5:1 and 3:1) followed by SCXchromatography [pre-wash column with methanol followed by DCM, loadmaterial dissolved in DCM, then elute with DCM/2M ammonia in methanol(1:1) and concentrate in vacuo] to obtain7-chloro-6-{[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethyl]-amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.

Use a method similar to the General Procedure 1-3 to deprotect7-chloro-6-{[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethyl]-amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by chromatography on silica gel eluting with DCM/2M ammonia inmethanol (99/1 to 90/10) to obtain the free base of the title compound.Use a method similar to the General Procedure 2-1 to give the titlecompound (184 mg, 42%). MS (ES+) m/z: 386 (M+H)⁺.

Examples 290-291 may be prepared essentially as described in Example 289by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

Yield MS Ex. O—R Compound (%) (ES+) m/z 290

7-Chloro-6-{[5(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-pyridin-2-ylmethyl]-amino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate48 414(M + H)⁺ 291

(±)-7-Chloro-6-{[5-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-2-ylmethyl]-amino}-2,3,4,5-tetrahydro-1H-benzo[d]azepinSuccinate 49 400(M + H)⁺

EXAMPLES 292 AND 293(−)-7-Chloro-6-{[5-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-2-ylmethyl]-amino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate and(+)-7-Chloro-6-{[5-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-2-ylmethyl]-amino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Separate the two enantiomers of(±)-7-chloro-6-{[5-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-2-ylmethyl]-amino}-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate by normal phase chiral HPLC (Chiralcel OD 8×35 cm, elute with4:1 heptane/3A-ethanol with 0.2% DMEA). Purify each enantiomer bychromatography on silica gel eluting with DCM/2M ammonia in methanol(20:1). Use a method similar to the General Procedure 2-1 to obtain thetitle compounds:(−)-7-Chloro-6-{[5-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-2-ylmethyl]-amino}-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate (Example 292, 75 mg, 38%), 95% ee [Chiralpak AD, 4.6×150 mm,eluent: 85/15 heptane/3A ethanol with 0.2% DMEA, 0.6 mL/min)]; MS (ES+)m/z: 400 (M+H)⁺. [α]²⁰ _(D) −12.1° (c 0.5, MeOH).(+)-7-Chloro-6-{[5-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-2-ylmethyl]-amino}-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate (Example 293, 72 mg, 37%), 93% ee [Chiralpak AD, 4.6×150 mm,eluent: 85/15 heptane/3A ethanol with 0.2% DMEA, 0.6 mL/min)]. MS (ES+)m/z: 400 (M+H)⁺. [α]²⁰ _(D) +7.4° (c 0.5, MeOH).

EXAMPLE 294(±)-7-Chloro-6-[(1-thiophen-2-yl-ethyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.47 mmol) with (±)-1-thiophen-2-yl-ethylamine (prepared asdescribed in J. Amer. Chem. Soc. 1942, 64, 477-479) (200 mg, 1.57 mmol).Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0,9:1 and 4:1) to give(±)-7-chloro-6-[(1-thiophen-2-yl-ethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(126 mg, 67%).

Use a method similar to the General Procedure 1-1, using(±)-7-chloro-6-[(1-thiophen-2-yl-ethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(126 mg, 0.313 mmol), to give the free base of the title compound (73mg, 77%). Use a method similar to the General Procedure 2-1, using(±)-7-chloro-6-[(1-thiophen-2-yl-ethyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(73 mg, 0.241 mmol) to give the title compound (100 mg, 50% overall). MS(ES+) m/z: 307 (+H)⁺.

EXAMPLE 295(+)-7-Chloro-6-[(1-thiophen-2-yl-ethyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate, Isomer 1

Separate the two enantiomers of(4)-7-chloro-6-[(1-thiophen-2-yl-ethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineby chiral preparative HPLC (Chiralpak AD, 8×30 cm; eluent: 9:1heptane/isopropanol with 0.2% DMEA; flow: 350 mL/min at 240 nm (UV),˜650 mg load] to obtain7-chloro-6-[(1-thiophen-2-yl-ethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1, ee=100% [Analytical Column: Chiralpak AD, 4.6×250 mm; eluent:9:1 heptane/isopropanol with 0.2% DMEA; flow: 1 mL/min at 250 nm (UV).

Use a method similar to the General Procedure 1-1, using7-chloro-6-[(1-thiophen-2-yl-ethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1, to give7-chloro-6-[(1-thiophen-2-yl-ethyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1. Use a method similar to the General Procedure 2-1, using7-chloro-6-[(1-thiophen-2-yl-ethyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1 (73 mg, 0.241 mmol) to give the title compound (100 mg, 98%).MS (ES+) m/z: 307 (M+H)⁺. [α]²⁰ _(D) +115.0° (c 0.5, MeOH).

EXAMPLE 296(±)-7-Chloro-6-[1-(5-methylthiophen-2-yl)ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(96 mg, 0.227 mmol) with (±)-2-(1-aminoethyl)-5-methylthiophene (48 mg,0.34 mmol) using palladium(II) acetate (10 mg, 0.0454 mmol), BINAP (60mg, 0.0908 mmol) and cesium carbonate (148 mg, 0.454 mmol) in toluene(10 mL). Purify by chromatography on silica gel eluting withhexane/EtOAc (1:0, 19:1) to give(±)-7-chloro-6-[1-(5-methylthiophen-2-yl)ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (47 mg, 50%). GC-MS m/z 416 (M⁺).

Use a method similar to the General Procedure 1-2, using(±)-7-chloro-6-[1-(5-methylthiophen-2-yl)ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(47 mg, 0.113 mmol) to give(±)-7-chloro-6-[1-(5-methylthiophen-2-yl)ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (30 mg, 83%) that was used without further purification. Use amethod similar to the General Procedure 2-1 to give the title compoundas a white solid (36 mg, 88% j. MS (ES+) m/z: 321 (M+H)⁺.

EXAMPLE 297(+)-7-Chloro-6-[1-(5-phenyl-thiophen-2-yl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.328 g, 0.773 mmol) with 15-phenyl-thiophen-2-yl)ethylamine Isomer 1(0.236 g, 1.16 mmol) using palladium(II) acetate (69 mg, 0.309 mmol),tris(dibenzylideneacetone)-dipalladium(0) (142 mg, 0.155 mmol), BINAP(578 mg, 0.928 mmol) and cesium carbonate (504 mg, 1.546 mmol) intoluene (10 mL). Purify by chromatography on silica gel eluting withhexane/EtOAc (1:0 and 19:1) to give7-chloro-6-[1-(5-phenyl-thiophen-2-yl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1 (89 mg, 34%).

Use a method similar to the General Procedure 1-2, using7-chloro-6-[1-(5-phenyl-thiophen-2-yl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1 (89 mg, 0.186 mmol) to give7-chloro-6-[1-(5-phenyl-thiophen-2-yl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1 (65 mg, 92%) as an oil that was used without furtherpurification. Use a method similar to the General Procedure 2-1, using7-chloro-6-[1-(5-phenyl-thiophen-2-yl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 1 (65 mg, 0.17 mmol), to give the title compound as a white solid(58 mg, 68%). MS (ES+) m/z: 383 (M+H)⁺; [α]²⁰ _(D) +159.0° (c 0.5,MeOH).

EXAMPLE 298(−)-7-Chloro-6-[1-(5-phenyl-thiophen-2-yl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.484 g, 1.138 mmol) with 1-(5-phenyl-thiophen-2-yl)ethylamine Isomer 2(0.347 g, 1.71 mmol) using palladium(II) acetate (102 mg, 0.45 mmol),tris(dibenzylideneacetone)-dipalladium(0) (209 mg, 0.228 mmol), BINAP(851 mg, 1.366 mmol) and cesium carbonate (741 mg, 2.276 mmol) intoluene (12 mL). Purify by chromatography on silica gel eluting withhexane:EtOAc (1:0 and 19:1) to give7-chloro-6-[1-(5-phenyl-thiophen-2-yl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 2 (247 mg, 63%).

Use a method similar to the General Procedure 1-2, using7-chloro-6-[1-(5-phenyl-thiophen-2-yl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 2 (247 mg, 0.516 mmol) to give7-chloro-6-[1-(5-phenyl-thiophen-2-yl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 2 (184 mg, 93%) as an oil that was used without furtherpurification. Use a method similar to the General Procedure 2-1, using7-chloro-6-[1-(5-phenyl-thiophen-2-yl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineIsomer 2 (184 mg, 0.48 mmol) to give the title compound as a white solid(200 mg, 83%). MS (ES+) m/z: 383 (M+H)⁺; [α]²⁰ _(D) −196.5° (c 0.5,MeOH).

EXAMPLE 299(±)-7-Chloro-6-[(1-thiophen-3-yl-ethyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.47 mmol) with (±)-1-thiophen-3-yl-ethylamine (prepared asdescribed in J. Heterocycl. Chem. 1988, 25, 1571-1581) (90 mg, 0.70mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc(1:0, 9:1 and 4:1) to give(±)-7-chloro-6-(1-thiophen-3-yl-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(100 mg, 53%).

Use a method similar to the General Procedure 1-1, using(±)-7-chloro-6-(1-thiophen-3-yl-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(100 mg, 0.248 mmol), to give the free base of the title compound (74mg, 98%). Use a method similar to the General Procedure 2-1, using(±)-7-chloro-6-(1-thiophen-3-yl-ethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(74 mg, 0.242 mmol) to give the title compound (108 mg, 54% overall). MS(ES+) m/z: 307 (M+H)⁺.

EXAMPLE 3007-Chloro-6-[(5-methylfuran-2-ylmethyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Combine7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(100 mg, 0.24 mmol), 2-(di-tert-butylphosphino)-biphenyl (6.8 mg, 0.023mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 0.012 mmol) andpotassium phosphate (70 mg, 0.33 mmol) in a pressure tube and degas.Dissolve the mixture in dry toluene (2 mL) and degas. Add a solution of5-methylfurfurylamine (30 mg, 0.27 mmol) in toluene (1 mL) and degas.Stir at 90° C. for 24 h. Cool to ambient temperature, dilute with ethylether and filter through Celite®. Concentrate and purify bychromatography on silica gel eluting with hexane/EtOAc (20:1). Removethe solvent and add 7M ammonia in methanol (4 mL). Stir at ambienttemperature for 24 h. Concentrate and purify by SCX chromatography togive the free base of the title compound. Use a method similar to theGeneral Procedure 2-2 to obtain the title compound as a solid (56 mg,66%). MS (ES+) m/z: 291 (M+H)⁺.

Examples 301-302 may be prepared essentially as described in Example 300by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

Yield MS Ex. R Compound (%) (ES+) m/z 301 4-Cl7-Chloro-6-{[3-(4-chlorophenyl)- 30 389 isoxazol-5-ylmethyl]-amino}-(M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Hydrochloride 302 4-OMe7-Chloro-6-{[3- 54 384 (4-methoxyphenyl)- isoxazol-5-ylmethyl]-amino}-(M + H)⁺ 2,3,4,5-tetrahydro-1H- benzo[d]azepine Hydrochloride

EXAMPLE 3037-Chloro-6-(thiazol-5-ylmethyl-amino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Thiazole-5-carbaldehyde: Add DMSO slowly to a solution of oxalylchloride (1.6 g, 13 mmol) in anhydrous DCM (30 mL) under nitrogen at−78° C. and stir for 10 min. Add dropwise a solution of5-hydroxymethylthiazole (1.15 g, 10 mmol) in DCM (10 mL) and stir themixture for 40 min. Add triethylamine and stir for 5 min and then quenchthe reaction with water. Extract the mixture three times with ether,combine the organic extracts, wash with brine, dry over Na₂SO₄, filterand concentrate in vacuo. Purify by chromatography on silica gel elutingwith EtOAc/hexane (2:5) to give thiazole-5-carbaldehyde (337 mg, 29%).3-(tert-Butoxycarbonyl)-7-chloro-6-(thiazol-5-ylmethyleneamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve6-amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(285 mg, 0.97 mmol) in methanol (10 mL). Add 7N ammonia in methanol (10mL) and stir overnight at ambient temperature. Concentrate in vacuo anddissolve the residue in THF (10 mL). Add saturated aqueous NaHCO₃ (5 mL)and di-tert-butyl-dicarbonate (254 mg, 1.16 mmol). Stir the reactionmixture at ambient temperature for 4 h. Dilute the mixture with water,extract three times with EtOAc, combine the organic extracts, dry overNa₂SO₄, filter and concentrate in vacuo to give crude material. Mixthiazole-5-carbaldehyde (165 mg, 1.45 mmol) with above crude residue(0.97 mmol, assuming 100% conversion), acetic acid (87 mg, 1.45 mmol)and 1,2-dichloroethane (10 mL). Stir at ambient temperature for 20 min.Add sodium triacetoxyborohydride and stir under nitrogen overnight.Quench the reaction with saturated aqueous NaHCO₃, separate the organiclayer and extract the aqueous layer three times with DCM. Combine theorganic extracts, dry over Na₂SO₄, filter and concentrate in vacuo.Purify by chromatography on silica gel eluting with EtOAc/hexane (1:3)to afford the desired intermediate as a yellow oil (228 mg, 60% threesteps). MS (ES+) m/z: 392 (M+H)⁺.3-(t-Butoxycarbonyl)-7-chloro-6-(thiazol-5-ylmethyl-amino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve3-(t-butoxycarbonyl)-7-chloro-6-(thiazol-5-ylmethyleneamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(228 mg, 0.58 mmol) in methanol (10 mL), add sodium borohydride (263 mg,7 mmol) and reflux for 28 h. Cool to ambient temperature, dilute withEtOAc and add slowly water. Separate the organic layer, extract theaqueous layer three times with EtOAc. Combine the organic extracts, dryover Na₂SO₄, filter and concentrate in vacuo. Purify by chromatographyon silica gel eluting with EtOAc/hexane (1:3) to give the desiredintermediate as a colorless oil (134 mg, 58%). MS (ES+) m/z: 394 (M+H)⁺.7-Chloro-§(thiazol-5-ylmethyl-amino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride: Use a method similar to the General Procedure 1-6 todeprotect3-(tert-butoxycarbonyl)-7-chloro-6-(thiazol-5-ylmethyl-amino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(134 mg, 0.34 mmol). Purify by chromatography on silica gel eluting withDCM/2M ammonia in methanol (94:6) to give7-chloro-6-(thiazol-5-ylmethyl-amino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (90 mg, 90%). MS (ES+) m/z: 294 (M+H)⁺. Use a method similarto the General Procedure 2-2 to obtain the title compound.

EXAMPLE 3047-Chloro-6-[(3-pyridyl)amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(300 mg, 0.7 mmol) with 3-aminopyridine (75 mg, 0.85 mmol). Purify bychromatography on silica gel eluting with hexane/EtOAc (4:1) to give7-chloro-6-[(3-pyridyl)amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an off-white solid (20 mg, 8%). MS (ES+) m/z: 370 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-[(3-pyridyl)amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(20 mg, 0.05 mmol). Purify by SCX chromatography to give7-chloro-6-[(3-pyridyl)amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as ayellow oil (15 mg, 99%). Use a method similar to the General Procedure2-1, using7-chloro-6-[(3-pyridyl)amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(15.1 mg, 0.05 mmol), to give the title compound as a light yellow solid(20 mg, 97%). MS (ES+) m/z: 319 (M+H)⁺.

EXAMPLE 3057,9-Dichloro-6-(3,4-difluorobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Dissolve7-dichloro-6-(3,4-difluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(150 mg, 0.36 mmol) in anhydrous toluene (20 mL). AddN-chlorosuccinimide (140 mg, 1 mmol) and heat at 60° C. for 4 h. Cool toroom temperature, pour reaction mixture into water (250 mL) and extractwith EtOAc (3×50 mL). Wash combined organic extracts with water, brine,dry over Na₂SO₄, filter, and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (4:1) to give7,9-dichloro-6-(3,4-difluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(110 mg, 67%). MS (ES+) m/z: 453 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7,9-dichloro-6-(3,4-difluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(120 mg, 0.26 mmol). Purify by SCX chromatography to give7,9-dichloro-6-(3,4-difluorobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (81 mg, 88%). Use a method similar to the GeneralProcedure 2-2, using7,9-dichloro-6-(3,4-difluorobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(75 mg, 0.21 mmol), to give the title compound as a yellow gum (80 mg,96%). MS (ES+) m/z: 357 (M+H)⁺.

EXAMPLE 3067-Chloro-9-fluoro-6-(3-fluorobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1 to couple7-chloro-9-fluoro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(130 mg, 0.3 mmol) with 3-fluorobenzylamine (100 □L, 0.89 mmol). Purifyby chromatography on silica gel eluting with hexane/EtOAc (9:1 and 4:1)followed by SCX chromatography to give7-chloro-9-fluoro-6-(3-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (35 mg, 28%). MS (ES+) m/z: 401 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-9-fluoro-6-(3-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(32 mg, 0.08 mmol). Purify by SCX chromatography to give7-chloro-9-fluoro-6-(3-fluorobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (10 mg, 45%). Use a method similar to the GeneralProcedure 2-1, using7-chloro-9-fluoro-6-(3-fluorobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(10 mg, 0.033 mmol), to give the title compound as a light yellow solid(14 mg, 97%). MS (ES+) m/z: 323 (M+H)⁺.

EXAMPLE 3077-Fluoro-6-(4-fluorobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(250 mg, 0.61 mmol) with 4-fluorobenzylamine (92 mg, 1.2 equiv.) usingpalladium(II) acetate (0.1 equiv.), BINAP (0.3 equiv.) and cesiumcarbonate (1.4 equiv.) in toluene (5 mL). Purify by chromatography onsilica gel eluting with hexane/EtOAc (10:1, 5:1, 3:1 and 1:1) to give7-fluoro-6-(4-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil.

Use a method similar to the General Procedure 1-3 to deprotect7-fluoro-6-(4-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by SCX chromatography to give the free base of the titlecompound. Use a method similar to the General Procedure 2-1 to give thetitle compound as an off white solid (14 mg, 6%). MS (ES+) m/z: 289(M+H)⁺.

EXAMPLE 308 6-Benzylamino-7-cyano-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1 to couple7-cyano-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(125 mg, 0.3 mmol) with benzylamine (0.1 mL, 0.9 mmol) usingpalladium(II) acetate (7 mg, 0.03 mmol), BINAP (37 mg, 0.06 mmol) andcesium carbonate (137 mg, 0.4 mmol) in toluene (3 mL). Purify bychromatography on silica gel eluting with heptane/EtOAc (4:1 to 1:1) togive6-benzylamino-7-cyano-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a clear oil (60 mg, 54%). ES (ES+) m/z: 374 (M+H)⁺.

Use a method similar to the General Procedure 1-2, using6-benzylamino-7-cyano-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(56 mg, 0.15 mmol), to give6-benzylamino-7-cyano-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clearoil (38 mg, 93%). MS (ES+) m/z: 278 (M+H)⁺. Use a method similar to theGeneral Procedure 2-1 to give the title compound as a white powder (39mg, 71%). MS (ES+) m/z: 278 (M+H)⁺.

Examples 309-310 may be prepared essentially as described in Example 308by using7-cyano-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

Yield MS Ex. R Compound (%) (ES+) m/z 309 4-F7-Cyano-6-(4-fluorobenzy]amino)- 46 296 2,3,4,5-tetrahydro-1H- (M + H)⁺310 2-F 7-Cyano-6-(2-fluorobenzy]amino)- 43 296 2,3,4,5-tetrahydro-1H-(M + H)⁺ benzo[d]azepine Succinate

EXAMPLE 3116-(3-Fluorobenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1 to couple3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(110 mg, 0.24 mmol) and 3-fluorobenzyl amine (90 μL, 0.7 mmol). Purifyby chromatography on silica gel eluting with hexane/EtOAc (95:5)followed by SCX chromatography to give6-(3-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (55 mg, 53%). MS (ES+) m/z: 435 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect6-(3-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(55 mg, 0.13 mmol). Purify by SCX chromatography to give6-(3-fluorobenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (34 mg, 81%). Use a method similar to the GeneralProcedure 2-1 to give the title compound as an off-white solid (33 mg,72%). MS (ES+) m/z: 339 (M+H)⁺.

EXAMPLE 312(S)-(−)-6-[1-(4-Fluorophenyl)-ethylamino]-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3 to couple3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(430 mg, 0.94 mmol) with (S)-1-(4-fluorophenyl)ethylamine (195 mg, 1.40mmol). Purify by chromatography on silica gel eluting with EtOAc/hexane(1:8) to give(S)-6-[1-(4-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(279 mg, 65%). MS (ES+) m/z: 449 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect(S)-6-[1-(4-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(279 mg, 0.62 mmol). Purify by chromatography on silica gel eluting withDCM/2M ammonia in methanol (94:6) to obtain(S)-6-[1-(4-fluorophenyl)-ethylamino]-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil (190 mg, 87%). MS (ES+) m/z: 353 (M+H)⁺. Use a methodsimilar to the General Procedure 2-1 to give the title compound. [α]²⁰_(D) −96.7° (c 0.5, MeOH).

EXAMPLE 313(S)-7-Ethyl-6-[1-(4-fluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3 to couple7-ethyl-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(335 mg, 0.8 mmol) and (S)-1-(4-fluorophenol)ethyl amine (557 mg, 4.0mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc(1:0, 9:1 and 17:3) to give(S)-7-ethyl-6-[1-(4-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(127 mg, 39%). MS (ES+) m/z: 409 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect(S)-7-ethyl-6-[1-(4-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by chromatography on silica gel eluting with DCM/2M ammonia inmethanol (93:7) to give(S)-7-ethyl-6-[1-(4-fluorophenyl)-ethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(70 mg, 72%). MS (ES+) m/z: 313 (M+H)⁺. Use a method similar to theGeneral Procedure 2-1 to obtain the title compound.

EXAMPLE 3147-Propyl-6-[(2-thienyl)methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 5-1 to couple7-propyl-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2-(aminomethyl)-thiophene. Purify by chromatography on silica geleluting with hexane/EtOAc (9:1 and 4:1) to give7-propyl-6-[(2-thienyl)methylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow solid. MS (ES+) m/z: 397 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-propyl-6-[(2-thienyl)methylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by SCX chromatography to give the free base of the title compoundas a yellow oil. Use a method similar to the General Procedure 2-2 togive the title compound as a light yellow solid. MS (ES+) m/z: 301(M+H)⁺.

General Procedure 7

Dissolve the appropriate substituted3-tert-butoxycarbonyl-6-dimethylcarbamoyl-thio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.0 equiv) in methanol (0.1-0.2 M solution). Add potassium hydroxide(32 equiv.) and heat the mixture at 50° C. for 2-8 h. Cool the reactionto ambient temperature and add the appropriate halide (1.0-5.0 equiv.).Stir the mixture at ambient temperature for 0.5-16 h. Remove the solventin vacuo and partition the residue between DCM and water. Extract theaqueous phase with DCM, combine the organic extracts, dry over Na₂SO₄,filter and concentrate. Purify by chromatography in silica gel elutingwith hexane/EtOAc mixtures to obtain the desired compound.

Preparation 1723-tert-Butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine

7-Chloro-6-dimethylthiocarbamoyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Place7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(64.3 g, 219 mmol) in acetone (450 mL) and water (200 mL) with K₂CO₃(91.8 g, 664 mmol) and dimethylthiocarbamoyl chloride (31.5 g, 255mmol). Stir at ambient temperature for 1.25 h. Add additionaldimethylthiocarbamoyl chloride (3 g, 24 mmol) and stir for an additional1.75 h at ambient temperature. Add more dimethylthiocarbamoyl chloride(0.7 g, 5.7 mmol) and water (150 mL) to the mixture and stir for 0.5 hat ambient temperature. Slowly add water (500 mL) to the reaction over 2h to promote crystallization and stir the resulting slurry at ambienttemperature for 1.5 h. Collect the solid by filtration to give thedesired intermediate (76 g, 91%).3-tert-Butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve7-chloro-6-dimethylthiocarbamoyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(55 g, 407 mmol) in diphenyl ether (1500 mL) and heat to 250° C. for 2.5h. Cool the reaction and dilute with methanol (308 mL). Add 1N aqueousNaOH (616 mL) and stir at 60° C. for 4 h Cool the reaction to ambienttemperature and extract between DCM (3×500 mL) and water (500 mL).Combine the organic extracts and add to 1N aqueous HCl (1 L). Stir thereaction at ambient temperature for 0.25 h then wash with hexane (5×400mL). Adjust the pH of the aqueous layer to 7.0 with 5N aqueous NaOH andmix the aqueous solution with DCM (2.5 L). Cool the mixture in an icebath and add K₂CO₃ (169 g, 1221 mmol) and di-t-butyl dicarbonate (67.5g, 390 mmol) and stir the reaction at ambient temperature for 0.5 h. Adddi-t-butyl dicarbonate (16.35 g, 75 mmol) and stir for 0.3 h at ambienttemperature. Add di-t-butyl dicarbonate (0.1 g, 0.46 mmol) and stir for0.25 h at ambient temperature. Concentrate the mixture in vacuo toremove the volatiles and warm to 45° C. Seed the mixture with a smallamount of the title compound and stir for 1 h at 45° C. Cool thereaction in an ice bath and stir for an additional 2 h. Collect theresultant solid by filtration and rinse with cold hexane (100 mL).Concentrate the filtrate in vacuo, recrystallize from DCM/heptane, andisolate the solids by filtration. Combine the solids and dry in vacuo togive the title compound as a white crystalline solid (142 g, 91%). MS(ES+) m/z 385 (M+H)⁺.

Preparation 1733-tert-Butoxycarbonyl-7-chloro-6-diethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine

7-Chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,4,5-tetrahydro-1H-benzo[d]azepineand7,9-dichloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

To a solution of6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.961 g, 3.71 mmol) in toluene (30 mL) at 70° C., add diisobutylamine(52 μL, 0.30 mmol) followed by slow addition of neat sulfuryl chloride(343 μL, 4.27 mmol). Stir for 1 h at 70° C. and concentrate in vacuo.Dilute the residue with water, extract three times with EtOAc, dry overanhydrous Na₂SO₄ and concentrate in vacuo to afford a 4:1 mixture of7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand7,9-dichloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a white solid (1.07 g, 98%).

7-Chloro-6-dimethylthiocarbamoyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand7,9-dichloro-6-dimethylthiocarbamoyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:To a mixture of 4:17-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand7,9-dichloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.513 g, 1.75 mmol) in anhydrous dioxane (10 mL) under nitrogen, adddimethyl thiocarbamoyl chloride (0.432 g, 3.50 mmol),4-dimethylaminopyridine (21 mg, 0.18 mmol) and triethylamine (731 μL,5.24 mmol) and heat under reflux overnight. Cool the reaction mixture toambient temperature and dilute with water, extract three times withEtOAc, dry over anhydrous Na₂SO₄ and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (17:1) to afforda mixture of 4:17-chloro-6-dimethylthiocarbamoyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand7,9-dichloro-6-dimethylthiocarbamoyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (0.64 g, 95%)

7-Chloro-6-dimethylcarbamoylthio-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand7,9-dichloro-6-dimethylcarbamoylthio-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzoazepine:Heat the mixture of 4:17-chloro-6-dimethylthiocarbamoyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand7,9-dichloro-6-dimethylthiocarbamoyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.630 g, 1.66 mmol) in diphenyl ether (4.5 mL) at 250° C. for 4 h undernitrogen. Cool to ambient temperature. Purify by chromatography onsilica gel eluting with hexane/EtOAc (7:3) to give a mixture of 4:17-chloro-6-dimethylcarbamoylthio-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand7,9-dichloro-6-dimethylcarbamoylthio-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (0.54 g, 85%).

3-tert-Butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine:To the mixture of 4:17-chloro-6-dimethylcarbamoylthio-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand7,9-dichloro-6-dimethylcarbamoylthio-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.536 g, 1.47 mmol) in methanol (7 mL), add aqueous potassium carbonate(0.812 g, 5.88 mmol in 1.5 mL of water). Stir for 5 h at ambienttemperature; add di-tert-butyl dicarbonate (418 mg, 1.91 mmol) and stirfor an additional 30 min. Dilute with EtOAc and water. Separate thelayers and extract the aqueous layer three times with EtOAc. Dry overanhydrous Na₂SO₄, and concentrate in vacuo. Purify by chromatography onsilica gel eluting with hexane/EtOAc (7:3) to give a mixture of 4:13-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a white solid (0.52 g, 96%).

Preparation 1747-Bromo-3-tert-butoxycarbonyl-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Use a method similar to the Preparation 172, using7-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give the title compound.

Preparation 1753-tert-Butoxycarbonyl-6-dimethylcarbamoylthio-7-methyl-2,3,4,5-tetrahydro-1H-benzo[a]azepine

7-Bromo-6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add potassium carbonate (10.214 g, 73.9 mmol) to a solution of7-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(5.0 g, 14.8 mmol) in acetone (50 mL) and stir for 10 min. Add methyliodide (4.2 g, 1.5 mL, 29.6 mmol) and stir the mixture overnight at roomtemperature. Remove the solvent in vacuo and partition the residuebetween water and DCM. Extract the aqueous phase twice with DCM. Combinethe organic extracts, dry over Na₂SO₄, filter and concentrate in vacuoto obtain the desired intermediate as a solid (5.15 g, 99%). MS (ES+)m/z: 352 (M+H)⁺.6-Methoxy-7-methyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add potassium carbonate (5.65 g, 40.91 mmol),tetrakis(triphenylphosphine)palladium (1.576 g, 1.363 mmol) andtrimethylboroxine (2.053 g, 2.3 mL, 16.35 mmol) to a solution of7-bromo-6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(4.8 g, 13.63 mmol) in dimethylformamide (40 mL) under nitrogen. Heatthe mixture to 115° C. for 6 h. Add water and extract the aqueous phasetwice with EtOAc. Combine the organic extracts, dry over Na₂SO₄, filterand concentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (1:0 and 19:1) to obtain the desired intermediate as asolid (3.23 g, 83%). GC-MS m/z 287 (M⁺).6-Hydroxy-7-methyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add borontribromide (21.6 mL, 1.0 M solution in DCM) to a solution of6-methoxy-7-methyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(3.1 g, 10.8 mmol) in DCM (200 mL) at 0° C. under nitrogen. Warm to roomtemperature and stir overnight. Dilute with DCM and wash with water. Drythe organic layer over Na₂SO₄, filter and concentrate in vacuo. Purifyby chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1)to obtain the desired intermediate as a solid (2.74 g, 93%). MS (ES+)m/z: 274 (M+H)⁺.6-Dimethylthiocarbamoyloxy-7-methyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve6-hydroxy-7-methyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.0 g, 3.66 mmol) in acetone (50 mL). Add potassium carbonate (1.517 g,10.98 mmol) and dimethylthiocarbamoyl chloride (0.904 g, 7.32 mmol).Heat the mixture at reflux overnight. Remove the solvent in vacuo andpartition the residue between water and DCM. Dry the organic phase overNa₂SO₄, filter and concentrate. Purify by chromatography on silica geleluting with hexane/EtOAc (1:0 and 9:1) to obtain the desiredintermediate as a solid (1.18 g, 90%). MS (ES+) m/z: 361 (M+H)⁺.6-Dimethylcarbamoylthio-7-methyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve6-dimethylthiocarbamoyloxy-7-methyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.15 g, 3.19 mmol) in diphenyl ether (20 mL) and heat to 265° C. for 3h in a sealed tube. Cool the reaction to room temperature. Purify bychromatography on silica gel eluting with hexane/EtOAc (4:1 and 7:3) toobtain the desired intermediate as a solid (1.10 g, 96%). MS (ES+) m/z:361 (M+H)⁺.3-tert-Butoxycarbonyl-6-dimethylcarbamoylthio-7-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve6-dimethylcarbamoylthio-7-methyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.048 g, 2.9 mmol) in methanol (40 mL). Add a solution of potassiumcarbonate (1.6 g, 11.6 mmol) in water (10 mL). Stir at room temperatureovernight. Remove the solvent and partition the residue between waterand DCM. Extract the aqueous phase twice with DCM. Combine the organicextracts, dry over Na₂SO₄, filter and concentrate. Dissolve the residue(0.756 g, 2.86 mmol) in DCM (50 mL). Add triethylamine (0.579 g, 0.8 mL,2.0 equiv) and di-tert-butyl dicarbonate (0.624 g, 2.86 mmol) and stirat room temperature overnight. Dilute with DCM and wash with water. Drythe organic phase over Na₂SO₄, filter and concentrate to obtain thetitle compound as foam (1.038 g, 99%). MS (ES+) m/z: 264 (M+H-Boc)⁺.

Preparation 1763-tert-Butoxycarbonyl-7-cyano-6-dimethylcarbamoylsulfanyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

7-Cyano-6-dimethylthiocarbamoyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add dimethylthiocarbamoyl chloride (197 mg, 1.58 mmol) to a stirredsolution of7-cyano-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(150 mg, 0.53 mmol), DMAP (6 mg, 0.05 mmol) and dry triethylamine (300μL) in dry 1,4-dioxane (5 mL) under an atmosphere of nitrogen and heatat 120° C. for 6 h. Cool and continue stirring for 2 days at ambienttemperature. Dilute with EtOAc, wash with 1N aqueous HCl, water,saturated aqueous Na₂CO₃ and brine. Dry over MgSO₄ then concentrate invacuo. Purify by chromatography on silica gel eluting with EtOAc:heptane(0:1 to 3:10) to give the desired intermediate as a white solid (158 mg,81%).7-Cyano-6-dimethylcarbamoylsulfanyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Heat a round bottom flask containing a solution of7-cyano-6-dimethylthiocarbamoyloxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(786 mg, 2.12 mmol) in diphenyl ether (21 mL) in a preheated oil bath at230° C. for 2 h. Cool and purify by chromatography on silica gel elutingwith EtOAc:heptane (0:1 to 1:1) to give the desired intermediate as ayellow foam (740 mg, 94%). ¹H NMR (300 MHz, CDCl₃) δ 7.60-7.56 (d, 1H),7.36-7.30 (d, 1H), 3.88-3.68 (m, 4H), 3.34-3.03 (m, 10H).3-tert-Butoxycarbonyl-7-cyano-6-dimethylcarbamoylsulfanyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add potassium carbonate (4.13 g, 30 mmol) to a stirred solution of7-cyano-6-dimethylcarbamoylsulfanyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(740 mg, 2.0 mmol) in methanol (40 mL)/water (15 mL) and stir for 1.5 h.Add DCM (10 mL), di-tert-butyl dicarbonate (480 mg, 2.2 mmol) and stirat ambient temperature for 3 days. Concentrate in vacuo and dilute withDCM, wash with water and extract with DCM. Combine the organic layers,wash with brine, dry over MgSO₄ and concentrate in vacuo. Purify bychromatography on silica gel eluting with EtOAc:heptane (0:1 to 1:1) togive the title compound as a colourless foam (370 mg, 50%). ¹H NMR (300MHz, CDCl₃) δ 7.52 (d, J=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 3.69-3.48 (m,4H), 3.26-3.02 (m, 10H), 1.45 (s, 9H).

Preparation 177(S)-3-tert-Butoxycarbonyl-7-chloro-6-(5-oxo-tetrahydro-furan-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

To a solution of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo[d]azepine(137 mg, 0.356 mmol) in methanol (2 mL) add potassium hydroxide pellets(640 mg, 11.4 mmol) and heat for 3 h at 50° C. Cool to ambienttemperature, add saturated aqueous NH₄Cl, extract three times withEtOAc, dry over anhydrous Na₂SO₄, and concentrate in vacuo. Dissolve thecrude thiophenol thus obtained in dry DMF (2 mL), and add with stirringsodium hydride (18 mg, 0.713 mmol, 95% dispersion), followed by(S)-(+)-dihydro-5-(p-tolylsulfonyloxymethyl)-2-(3H)-furanone (144 mg,0.533 mmol). Continue stirring overnight at ambient temperature, thendilute cautiously with EtOAc and cold saturated aqueous NH₄Cl. Extractthree times with EtOAc, dry over anhydrous Na₂SO₄, and concentrate invacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc(7:3) to give the title compound as a colorless oil.

Preparation 178 5-Chloromethyl-3-methyl-[1,2,4]oxadiazole

Add with stirring hydroxylamine (50% in water, 25.0 mL, 0.380 mol) to asolution of acetonitrile (5.0 mL, 95.0 mmol) and ethanol (500 mL). Heatat 70° C. for 18 h. Concentrate in vacuo to provide crudeN-hydroxyacetamidine (7.0 g, 100%). Add slowly with stirring vinylchloroacetate (2.1 mL) to N-hydroxyacetamidine (J. Org. Chem. 1971, 36,1306-1307) (1.00 g, 13.5 mmol) and heat at 90° C. for 5 h. Cool toambient temperature, dilute with DCM, wash with aqueous 1N aqueous NaOH,dry over anhydrous Na₂SO₄ and concentrate in vacuo to give the titlecompound (904 mg, 50%).

The compounds of Preparation 179-182 were prepared essentially asdescribed in Preparation 178.

Prep. Structure Compound 179

3-tert-Butyl-5-chloromethyl-[1,2,4]oxadiazole 180

5-Chloro-methyl-3-propyl-[1,2,4]oxadiazole 181

5-Chloro-methyl-3-(4-chloro-phenyl)-[1,2,4]oxadiazole 182

2-(5-Chloro-methyl-[1,2,4]oxadiazol-3-yl)-pyridine

Preparation 183 2-Bromomethyl-6-chloropyridine

Heat a mixture of 2-chloro-6-methylpyridine (5.46 g, 42.8 mmol), NBS(8.38 g, 47.08 mmol), and benzoyl peroxide (500 mg, 2.06 mmol) in carbontetrachloride (80 mL) for 20 h at 85° C. Cool to ambient temperature,filter, and concentrate in vacuo. Purify by chromatography on silica geleluting with hexane/toluene (4:3) to provide the title compound as awhite solid (3.64 g, 41%).

Preparation 184 3-Bromo-2-bromomethyl-pyridine

Heat a mixture of 3-bromo-2-methylpyridine (J. Med. Chem. 1987, 30,871-880) (2.7 g, 15.8 mmol), NBS (3.10 g, 17.42 mmol), and benzoylperoxide (190 mg, 0.78 mmol) in carbon tetrachloride (50 mL) overnightat 85° C. Cool to ambient temperature, filter, and concentrate in vacuo.Purify by chromatography on silica gel eluting with toluene to providethe title compound as a white solid (1.81 g, 45%).

Preparation 185 2-Bromo-6-bromomethyl-pyridine

Use a method similar to the Preparation 184, using2-bromo-6-methylpyridine, to give the title compound.

Preparation 186 5-Bromo-2-bromomethylpyridine

2-Hydroxymethyl-5-bromopyridine: Dissolve 2,5-dibromopyridine (10 g, 42mmol) in toluene (500 mL) and cool to −78° C. Add 2.5M n-butyllithium inhexane (20.3 mL, 50.6 mmol) and stir the mixture for 7 h at the sametemperature. Add DMF (4.2 mL, 54.87 mmol) and stir for 1 h. Warm thesolution to 0° C. and add sodium borohydride (3.2 g, 84.42 mmol). Stirthe mixture at ambient temperature for 3 h. Dilute with EtOAc andsaturated aqueous NH₄Cl. Separate the layers and extract the aqueouslayer three times with EtOAc. Dry over anhydrous Na₂SO₄, filter andconcentrate in vacuo. Recrystallization from hexane/EtOAc (9:1) givesthe desired intermediate as a white solid (5.3 g, 66%).5-Bromo-2-bromomethyl-pyridine: Dissolve 2-hydroxymethyl-5-bromopyridine(5.21 g, 27.7 mmol) in 48% aqueous hydrobromic acid (20 mL). Heat themixture at 150° C. for 2 h. Cool to ambient temperature and removeexcess hydrobromic acid under vacuum. Dilute with water, add cautiouslysaturated aqueous NaHCO₃ and extract three times with EtOAc. Dry overanhydrous Na₂SO₄, filter and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (9:1) to give thetitle compound as pink oil (6.0 g, 87%) that crystallizes in thefreezer.

Preparation 187 2-Chloromethyl-3-methylpyridine Hydrochloride

2-Hydroxymethyl-3-methylpyridine: Heat a mixture of 3-methylpicolinicacid (1.0 g, 7.3 mmol), potassium carbonate (4.1 g, 29.7 mmol), andiodomethane (4.4 g, 31.0 mmol) in acetone (35 mL) overnight underreflux. Filter, wash the residue with EtOAc, and concentrate in vacuo.Pass through a short plug of silica gel eluting with hexane/EtOAc (1:1)to provide 2-methoxycarbonyl-3-methylpyridine as a pale yellow liquid(630 mg, 57%). To a solution of 2-methoxycarbonyl-3-methylpyridine inanhydrous THF (10 mL) at 0° C., add with stirring a solution of 1Mlithium aluminum hydride in THF (5 mL, 5 mmol), and continue stirringfor 30 min at 0° C. Allow the mixture to warm to ambient temperature andquench cautiously with 0.5M aqueous NaOH. Heat the mixture at 60° C. for40 min, cool to ambient temperature, extract with EtOAc, dry overanhydrous Na₂SO₄ and concentrate in vacuo. Purify by chromatography onsilica gel eluting with hexane/EtOAc (4:3) to give the desiredintermediate (90 mg, 18%).2-Chloromethyl-3-methylpyridine hydrochloride: To2-hydroxymethyl-3-methylpyridine (90 mg, 0.73 mmol) in dry DCM (10 mL)at ambient temperature, add with stirring thionyl chloride (0.53 mL, 7.3mmol). Continue stirring overnight, concentrate in vacuo, and azeotropethree times with chloroform. Triturate the residue with dry ether,filter, and dry under vacuum to obtain the title compound as a beigesolid (130 mg, 100%).

Preparation 188 2-Chloromethyl-6-Methylpyridine

Add with stirring a solution of thionyl chloride (0.77 mL, 10.6 mmol) indry DCM (20 mL) to 2-hydroxymethyl-6-methylpyridine (1.0 g, 8.12 mmol)in dry DCM (20 mL) at 0° C. Continue stirring at 0° C. for 1.25 h.Quench with isopropanol and concentrate in vacuo. Dissolve the residuein DCM, wash with saturated aqueous NaHCO₃, dry over anhydrous Na₂SO₄,and concentrate in vacuo to give the title compound. MS (ES+) m/z 142(M+H)⁺.

Preparation 189 5-Butyl-2-chloromethylpyridine Hydrochloride

Use a method similar to the Preparation 187, using fusaric acid, to givethe title compound. MS (APCI+) m/z 184 (M+H)⁺.

Preparation 190 6-Bromomethylnicotinonitrile

Use a method similar to the Preparation 184, using5-cyano-2-methylpyridine, to give the title compound.

Preparation 191 5-Bromomethyl-pyridine-2-carbonitrile

Use a method similar to the Preparation 184, using5-methyl-picolinonitrile (J. Chem. Soc. 1962, 2637-2658), to give thetitle compound.

Preparation 192 2-Chloromethyl-3-trifluoromethylpyridine Hydrochloride

Use the chlorination method described in Preparation 187, using2-hydroxymethyl-3-trifluoromethylpyridine, to give the title compound.MS (APCI+) m/z 196 (M+H)⁺.

Preparation 193 2-Chloromethyl-3-methoxypyridine

2-Hydroxymethyl-3-methoxypyridine: Heat a mixture of 3-hydroxypicolinicacid (5.3 g, 38 mmol), potassium carbonate (15.8 g, 114 mmol), andiodomethane (9.6 mL, 153 mmol) in acetone (100 mL) and DMF (10 mL)overnight at 60° C. Cool the reaction mixture to ambient temperature,pour into brine, extract three times with ethyl ether, dry overanhydrous MgSO₄ and concentrate in vacuo. Pass through a short plug ofsilica gel eluting with ether to provide3-methoxy-2-methoxycarbonylpyridine as a pale yellow liquid (6.3 g,100%). To a solution of 3-methoxy-2-methoxycarbonyl-pyridine (2.34 g,14.0 mmol) in dry THF (25 mL) add slowly with stirring a solution of 1Mlithium aluminum hydride in THF (10 mL, 10 mmol) and continue stirringovernight at ambient temperature. Quench cautiously with sodium sulfatedecahydrate, filter under suction and rinse the solids with additionalTHF. Concentrate in vacuo. Purify by chromatography on silica geleluting with hexane/EtOAc (3:1) to provide the desired intermediate as awhite solid (350 mg, 18%).2-Chloromethyl-3-methoxypyridine: Use a method similar to thePreparation 188, using 2-hydroxymethyl-3-methoxypyridine, to give thetitle compound. MS (APCI+) m/z 158 (M+H)⁺.

Preparation 194 2-Chloromethyl-6-methoxypyridine Hydrochloride

2-Hydroxymethyl-6-methoxypyridine: To 6-methoxy-pyridine-2-carbaldehyde(J. Org. Chem. 1990, 55, 69-73) (11.0 g, 80.3 mmol) in wet THF (200 mL)add portion wise with stirring sodium borohydride (3.0 g, 79 mmol) andcontinue stirring for 1 h at ambient temperature. Add brine, extract thereaction mixture twice with EtOAc, dry the organic layer over anhydrousNa₂SO₄ and concentrate in vacuo. Pass the residue through a small plugof silica gel eluting with hexane/EtOAc (3:1) to provide the desiredintermediate as a clear liquid (9.0 g, 81%).2-Chloromethyl-6-methoxypyridine hydrochloride: Use the chlorinationmethod described in Preparation 187, using2-hydroxymethyl-6-methoxypyridine, to give the title compound as a paleyellow solid. MS (APCI+) m/z 158 (M+H)⁺.

Preparation 195 3-Bromomethyl-6-chloro-pyridazine

Use a method similar to the Preparation 184, using3-chloro-6-methylpyridazine, to give the title compound as a red-orangeliquid that darkens on standing.

Preparation 196 (±)-2-(1-Chloroethyl)-3-cyanothiophene

2-Acetyl-3-cyanothiophene: Heat a stirred solution of2-acetyl-3-bromothiophene (1.49 g, 7.29 mmol) (Chem. Pharm. Bull. 2000,48, 1558-1566) in dry NMP (72 mL) for 10 h at 150° C. in the presence ofcopper cyanide (3.26 g, 36.5 mmol). Dilute the mixture with water,extract three times with diethyl ether, dry over anhydrous Na₂SO₄ andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (10:1) to give the desired intermediate as a dark oil(1.1 g, 99%).(±)-2-(1-Hydroxyethyl)-3-cyanothiophene: Use a method similar to thereduction procedure described in Preparation 194, using2-acetyl-3-cyanothiophene, to give the desired intermediate as dark oil.(±)-2-(1-Chloroethyl)-3-cyanothiophene: Use a method similar to thePreparation 188, using (±)-2-(1-hydroxyethyl)-3-cyanothiophene, to givethe title compound as dark oil. Use the crude material without furtherpurification.

Preparation 197 (+)-2-(1-Bromoethyl)-pyridine

To (±)-2-(1-hydroxyethyl)-pyridine (Bull. Chem. Soc. Jpn. 1990, 63,461-465) (10.0 g, 81.3 mmol) in DCM (120 mL) at 0° C., add with stirringtriphenylphosphine (22.39 g, 85.365 mmol) followed by NBS (15.2 g, 85.4mmol) in portions. Warm the reaction mixture to ambient temperature andcontinue stirring for 3 h. Concentrate in vacuo and purify bychromatography on silica gel eluting with hexane/EtOAc (19:1) to givethe title compound.

Preparation 198 (±)-2-(1-Chloroethyl)-6-methylpyridine Hydrochloride

(±)-2-(1-Hydroxyethyl)-6-methylpyridine: To6-methylpyridine-2-carboxaldehyde (2.0 g, 16.5 mmol) in dry THF (55 mL)at 0° C. under nitrogen, add a solution of 3M methyl magnesium bromidein ether (6.0 mL, 18.0 mmol) dropwise with stirring. After 1 h at 0° C.,quench with saturated aqueous NH₄Cl, extract three times with EtOAc, dryover anhydrous Na₂SO₄ and concentrate in vacuo to give the desiredintermediate (crude, 2.3 g).(±)-2-(1-Chloroethyl)-6-methylpyridine hydrochloride: To the crude2-(1-hydroxyethyl)-6-methylpyridine (1.6 g, 11.7 mmol) in dry DCM (15mL) add with stirring thionyl chloride (2.0 mL, 27 mmol) and continuestirring overnight Concentrate in vacuo, azeotrope three times with drychloroform and dry under high vacuum to provide the title compound as atan solid (1.9 g, 85%). MS (APCI+) m/z 156 (M+H)⁺.

Preparation 199 (R)-Methanesulfonic acid 1-(6-methyl-pyridin-2-yl)-ethylester

(±)-1-(6-Methyl-pyridin-2-yl)-ethanol: Use a method similar to thePreparation 198 (Step 1), using 6-methyl-2-pyridinecarboxaldehyde andmethylmagnesium bromide, to give the desired intermediate.(R)-1-(6-Methyl-pyridin-2-yl)-ethanol: Stir a mixture of1-(6-methyl-pyridin-2-yl)-ethanol (2.9 g, 21 mmol), 4 A molecular sievespowder (3 g), vinyl acetate (6 mL) and lipase Candida Antarctica acrylicresin (0.87 g) in i-Pr₂O (40 mL) at ambient temperature overnight (J.Org. Chem. 1998, 63, 2481-2487; Synlett 1999, 41-44). Remove the solidresidue by filtration. Evaporate the volatile substances and purify bychromatography eluting with hexane/EtOAc (7:3 to 1:1) to give the fastereluting (R)-acetic acid 1-(6-methyl-pyridin-2-yl)-ethyl ester ascolorless oil (1.9 g, 50%), and the slower eluting (S)-alcohol as lightyellow oil (1.258 g, 43%). Dissolve (R)-acetic acid1-(6-methyl-pyridin-2-yl)-ethyl ester (1.72 g, 9.62 mmol) in methanol(50 mL) and add potassium carbonate (5.3 g, 38.5 mmol) in water (10 mL).Stir the mixture at ambient temperature for 4 h. Dilute with brine,extract three times with EtOAc, dry over anhydrous Na₂SO₄, filterthrough a short pad of silica gel and concentrate in vacuo to give thedesired intermediate as a colorless oil (1.17 g, 89%).(R)-Methanesulfonic acid 1-(6-methyl-pyridin-2-yl)-ethyl ester: To astirred solution of (R)-1-(6-methyl-pyridin-2-yl)-ethanol (175 mg, 1.28mmol) and triethylamine (355 μl, 2.56 mmol) in DCM (5 mL) at 0° C. addmethanesulfonyl chloride (148 μl, 1.92 mmol). Stir at 0° C. for 30 minand quench the reaction mixture with saturated aqueous NaHCO₃ at thesame temperature. Extract the mixture three times with EtOAc, dry overanhydrous Na₂SO₄, and concentrate in vacuo. Purify by chromatography onsilica gel eluting with hexane/EtOAc (8:2) to give the title compound asa colorless oil (274 mg, 100%).

Preparation 200 (±)-2-(1-Bromoethyl)-3-methyl-pyridine

(±)-1-(3-Methyl-pyridin-2-yl)ethanol: Dissolve N,N-dimethylethanolamine(70.45 mmol) in hexane (90 mL) at 0° C., add 2.5M n-butyl lithium inhexane (140.9 mmol,) and stir for 30 min at this temperature. Add asolution of 3-picoline (35.23 mmol) in hexane (10 mL) and continuestirring at 0° C. for 1 h. Cool the resulting mixture to −78° C., addacetaldehyde (70.45 mmol) and continue stirring at −78° C. for 1 h.Dilute with water, warm to ambient temperature, extract three times withEtOAc, dry over anhydrous Na₂SO₄, and concentrate in vacuo. Purify bychromatography eluting with hexane/EtOAc (85:15) to give the desiredintermediate as a light yellow oil.(±)-2-(1-Bromoethyl)-3-methyl-pyridine: Use a method similar to thePreparation 197, using 1-(3-fluoro-pyridin-2-yl)-ethanol, to give thetitle compound.

Preparation 201(±)-2-[1-Methanesulfonyloxy-(2,2,2-trifluoroethyl)]pyridine

(±)-2-[1-Hydroxy-(2,2,2-trifluoroethyl)]-pyridine: To a stirred solutionof 2-pyridine carboxaldehyde (2.09 g, 19.5 mmol) and(trifluoromethyl)trimethylsilane (3.33 g, 23.4 mmol) in THF (30 mL) at0° C. add 1M tetrabutylammonium fluoride in THF (956 μl, 0.956 mmol).Continue stirring for 30 min at 0° C. and then at ambient temperaturefor 2 h. Add 1M aqueous HCl (20 mL) and stir 2 h at ambient temperature.Dilute with aqueous 1M aqueous NaOH to pH 8, extract the mixture threetimes with EtOAc, dry over anhydrous Na₂SO₄, and concentrate in vacuo.Purify by chromatography eluting with hexane/EtOAc (8:2) to give thedesired intermediate as a yellow oil (3.22 g, 93%).(±)-2-[1-Methanesulfonyloxy-(2,2,2-trifluoroethyl)]pyridine: Use amethod similar to the Preparation 199 (Step 3), using(−)-2-[1-hydroxy-(2,2,2-trifluoroethyl)]pyridine, to give the titlecompound.

Preparation 202 (±)-2-(1-Bromopropyl)pyridine

(±)-1-Pyridin-2-yl-propan-1-ol: To a stirred solution of 2-pyridinecarboxaldehyde (4.0 g, 37.34 mmol) in THF (50 mL) at 0° C., add 3M ethylmagnesium bromide in ether (18.7 mL, 56.0 mmol), continue stirring for30 min at 0° C. and then at ambient temperature for 2 h. Add water (200mL), extract three times with EtOAc, dry over anhydrous Na₂SO₄, filterthrough a short pad of silica gel and concentrate in vacuo to give thedesired intermediate as a yellow oil (3.39 g, 66%).(±)-2-(1-Bromopropyl)pyridine: Use a method similar to the Preparation197, using 1-pyridin-2-yl-propan-1-ol, to give the title compound.

Preparation 203 (±)-1-Pyridazin-3-yl-ethanol

3-(1-Ethoxyvinyl)pyridazine: Heat pyridazine-3-chloride (WO 0107416) (2g, 17.5 mmol) with tributyl-(1-ethoxyvinyl)tin (7.1 mL, 21.1 mmol) anddichlorobis(triphenylphosphine)palladium(II) (1.1 g, 1.6 mmol) in DMF(18 mL) at 110° C. for 13 h. Cool the mixture, dilute with ether (175mL) and add a solution of potassium fluoride (5.43 g, 94 mmol) in water(10 mL). After 1 h, filter the mixture through Celite®, and wash thefiltrate with brine. Dry the combined organic extracts over Na₂SO₄ andevaporate. Purify by chromatography on silica gel eluting withEtOAc:hexane (0:1 to 6:4) to obtain the desired intermediate (1.7 g,65%). HPLC t_(R)=3.7 min (Zorbax Eclipse XBD-C8 4.6×150 mm 5 microncolumn, 1.5 mL/min of 90/10 to 10/90 0.1% TFA in water/acetonitrile over10 min. Detector is at 230 and 254 nm.).1-Pyridazin-3-yl-ethanone: Stir 3-(1-ethoxyvinyl)pyridazine (1.7 g, 11.3mmol) in acetone (6.3 mL) and 2.5N aqueous HCl (3.1 mL) for 2 h atambient temperature and evaporate. Dissolve the residue in DCM and washthe organic layer with saturated aqueous NaHCO₃, dry the organic layerover Na₂SO₄ and evaporate to obtain the desired intermediate (1.4 g,99%). HPLC t_(R)=1.9 min (Zorbax Eclipse XBD-C8 4.6×150 mm 5 microncolumn, 1.5 mL/min of 90/10 to 10/90 0.1% TFA in water/acetonitrile over10 min. Detector is at 230 and 254 nm.).(±)-1-Pyridazin-3-yl-ethanol: To 1-pyridazin-3-yl-ethanone (1.4 g, 11.2mmol) in methanol (112 mL) add sodium borohydride (0.85 g, 22.5 mmol) at0° C. and stir for 1 h at ambient temperature. Evaporate the mixture andpurify by chromatography on silica gel eluting with EtOAc:hexane (1:1 to1:0) and methanol:EtOAc (0:1 to 1:9) to obtain the title compound (1.3g, 93%).

Preparation 204 (R)-(−)-1-(2-Pyridin-2-yl)ethanol methanesulfonate ester

(R)-1-(Pyridin-2-yl)-ethanol: Stir a mixture of(±)-1-(pyridin-2-yl)-ethanol (21.2 mmol), 4 A molecular sieves powder (3g), vinyl acetate (6 mL) and lipase Candida Antarctica acrylic resin(0.87 g) in i-Pr₂O (40 mL) at ambient temperature overnight-(J. Org.Chem. 1998, 63, 2481-2487; Synlett 1999, 41-44). Remove the solidresidue by filtration. Evaporate the volatile substances and purify bychromatography eluting with hexane/EtOAc (7:3 to 1:1) to give the fastereluting (R)acetic acid 1-(pyridin-2-yl)-ethyl ester as colorless oil(50%) and the slower eluting (S)-alcohol as light yellow oil (43%).Dissolve (R)-acetic acid 1-(pyridin-2-yl)-ethyl ester (9.620 mmol) inmethanol (50 mL) and add potassium carbonate (38.48 mmol) in water (10mL). Stir the mixture at ambient temperature for 4 h. Dilute with brine,extract three times with EtOAc, dry over anhydrous Na₂SO₄, filterthrough a short pad of silica gel and concentrate in vacuo to give thedesired intermediate as a colorless oil (89%).(R)-(−)-1-(2-Pyridinyl)ethanol methanesulfonate ester: To a stirredsolution of (R)-1-(pyridin-2-yl)-ethanol (1.28 mmol) and triethylamine(2.56 mmol) in DCM (5 mL) at 0° C. add methanesulfonyl chloride (1.92mmol). Stir at 0° C. for 30 min and quench the reaction mixture withsaturated aqueous NaHCO₃ at the same temperature. Extract three timeswith EtOAc, dry over anhydrous Na₂SO₄, and concentrate in vacuo. Purifyby chromatography on silica gel eluting with hexane/EtOAc (4:1) to givethe title compound as a colorless oil (100%). MS (APCI+) m/z 202 (M+H)⁺;[α]_(D) ²⁵=−73.5° (c 1, CHCl₃).

Preparation 205 (±)-1-(4-Fluorophenyl)ethyl bromide

Method A: Add carbon tetrabromide (646 mg, 1.95 mmol) to a solution oftriphenylphosphine (511 mg, 1.95 mmol) and (±)-4-fluoro-α-methylbenzylalcohol (260 mg, 1.86 mol) in dry DMF (20 mL) at 0° C. under nitrogen.Stir the reaction for 2 h to give the title compound. No furtherpurification required.Method B: Add HBr (460 μL of 48% W/W in water, 4.28 mmol) to a solutionof (±)-4-fluoro-α-methylbenzyl alcohol (300 mg, 2.14 mmol) in dry DCM(10 mL) at ambient temperature under an atmosphere of nitrogen. Stir for2.5 h. Reduce volume in vacuo to give the title compound. Dilute withDCM (1 mL) and use without further purification.

Preparation 206 (±)-2-(1-Bromoethyl)benzonitrile

Use a method similar to the Preparation 184, using 2-ethylbenzonitrile,to give the title compound as a clear liquid.

Preparation 207 1-(4-Bromomethylphenyl)-3,3-dimethylbutan-1-one

(±)-3,3-Dimethyl-1-p-tolylbutan-1-ol: To a stirred solution of4-methylbenzaldehyde (1.51 g, 12.6 mmol) in THF (30 mL) at 0° C., addneopentyl magnesium chloride (33.0 mL, 16.34 mmol, 0.5-1M in ether) andcontinue stirring at 0° C. for 1 h. Dilute with saturated aqueous NH₄Cl,extract three times with EtOAc, dry over anhydrous Na₂SO₄, andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (95:5) to give the desired intermediate as a colorlessoil (2.15 g, 89%).3,3-Dimethyl-1-p-tolyl-butan-1-one: To a stirred solution of(±)-3,3-dimethyl-1-p-tolyl-butan-1-ol (2.15 g, 11.3 mmol) in hexane (30mL) add manganese dioxide (2.94 g, 33.8 mmol) and heat the mixtureovernight at 65° C. Cool to ambient temperature, filter the manganesesalts, and concentrate in vacuo to give the desired intermediate as acolorless oil (2.2 g, 100%).1-(4-Bromomethylphenyl)-3,3-dimethylbutan-1-one: Use a method similar tothe Preparation 184, using 3,3-dimethyl-1-p-tolylbutan-1-one, to givethe title compound.

Preparation 208 1-(Bromomethylphenoxy)-3,3-dimethylbutan-2-one

1-(4-Hydroxymethylphenoxy)-3,3-dimethylbutan-2-one: Mix potassiumcarbonate (2.764 g, 20 mmol), 4-hydroxy-benzyl alcohol (1.49 g, 12 mmol)in absolute ethanol (100 mL), add 1-bromopinacolone (1.791 g, 10 mmol)dropwise. Heat the mixture under reflux for 12 h. Add water to dissolvethe solid, and remove most of the ethanol in vacuo. Extract the mixturewith EtOAc three times. Combine the organic layers, wash with brine, dryover Na₂SO₄, filter and concentrate. Purify the residue bychromatography on silica gel eluting with EtOAc:hexane (1:2) to providethe desired intermediate as a colorless oil (1.08 g, 48%). MS (ES+) m/z:205 (M+H—H₂O)⁺.1-(4-Bromomethylphenoxy)-3,3-dimethylbutan-2-one: Add phosphoroustribromide (1.45 g, 5.34 mmol) slowly to a solution of1-(4-hydroxymethyl-phenoxy)-3,3-dimethylbutan-2-one (1.08 g, 4.85 mmol)in anhydrous THF under nitrogen at 0° C. Stir at 0° C. for 1 h and thenraise to ambient temperature. Stir overnight. Dilute with EtOAc, washwith saturated aqueous NaHCO₃, brine, dry over Na₂SO₄, filter andconcentrate. Purify the residue by chromatography on silica gel elutingwith EtOAc:hexane (1:6) to provide the title compound (1.152 g, 83%). MS(ES+) m/z: 205 (M-Br)⁺.

Preparation 2091-(4-Bromomethyl-3-chlorophenoxy)-3,3-dimethylbutan-2-one

3-Chloro-4-hydroxybenzyl alcohol: Add a solution of DIBAL-H in toluene(1.0 M, 35 mL) to a solution of methyl 3-chloro-4-hydroxybenzoate (1.9g, 10 mmol) at 0° C. under nitrogen. Stir the reaction at 0° C. andgradually warm to ambient temperature overnight. Quench the reactionwith slow addition of 0.1N aqueous HCl, add more acid to break thegel-like solid to two clear layers. Separate the organic layer, andextract the aqueous layer with EtOAc three times. Combine the organiclayers, wash with brine, dry over Na₂SO₄, filter and concentrate to givea white solid. MS (ES−) m/z 157 (M−H)⁻.1-(4-Bromomethyl-3-chlorophenoxy)-3,3-dimethyl-butan-2-one: Use a methodsimilar to the Preparation 208 to convert 3-chloro-4-hydroxy-benzylalcohol to the title compound (1.144 g, 64% two steps). MS (ES+) m/z319.0 (M+H)⁺.

Preparation 210 1-Bromomethyl-4-(2,2-dimethyl-propoxy)-benzene

1-(2,2-Dimethyl-propoxy)-4-methyl-benzene: To a solution of p-cresol(526 mg, 4.87 mmol) in THF (50 mL), add with stirring diisopropylazodicarboxylate (2.16 mL, 10.7 mmol) followed by triphenylphosphine(306 mg, 11.7 mmol) and neopentyl alcohol (5.15 g, 58.4 mmol). Heat at60° C. for 3 h, cool to ambient temperature and concentrate in vacuo.Purify by chromatography on silica gel eluting with hexane/EtOAc to givethe desired intermediate as a colorless oil.1-Bromomethyl-4-(2,2-dimethyl-propoxy)-benzene: Use a method similar tothe Preparation 184, using 1-(2,2-dimethyl-propoxy)-4-methylbenzene, togive the title compound.

Preparation 211 1-Bromomethyl-2-methanesulfonylbenzene

(2-Methanesulfonylphenyl)methanol: To a stirred solution of2-methanesulfonyl-benzoic acid (2.7 g, 13.5 mmol) in dry THF (60 mL) at0° C., add a solution of borane in THF (27.0 mL, 0.5 M, 13.5 mmol).Allow the mixture to warm to ambient temperature and continue stirringfor 2 days. Quench the excess borane by slow addition of methanol, addbrine, extract three times with EtOAc, dry over anhydrous Na₂SO₄ andconcentrate in vacuo to provide the crude desired intermediate as aclear, thick oil (2.4 g, 97%).1-Bromomethyl-2-methanesulfonylbenzene: To a stirred solution of(2-methanesulfonyl-phenyl)methanol (735 mg, 3.99 mmol) in dry DCM (2 mL)at 0° C., add a solution of 1M phosphorous tribromide in DCM (6.0 mL,6.0 mmol) and continue stirring for 1 h. Dilute with saturated aqueousNaHCO₃, extract three times with ethyl ether, dry over anhydrous MgSO₄and concentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (12:1) to provide the title compound as a white solid(950 mg, 97%).

Preparation 2121-Bromomethyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio)benzene

Methanesulfonic acid 3,3,3-trifluoro-2-methyl-2-trifluoromethyl-propylester: To 2,2-bis(trifluoromethyl)propanol (4.34 g, 22.1 mmol) in DCM(100 mL) at 0° C. add with stirring triethylamine (6.2 mL, 44 mmol)followed by methanesulfonyl chloride (2.6 mL, 33 mmol). After 15 min at0° C. dilute with water and extract three times with EtOAc. Dry overanhydrous Na₂SO₄ and concentrate in vacuo to give the crude desiredintermediate as a yellow oil (6.16 g, 100%).1-Methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio)benzene:In a sealed tube dissolve 4-methylbenzenethiol (4.13 g, 33.2 mmol) inDMF (20 mL) at ambient temperature. Add portionwise with stirring sodiumhydride (899 mg, 37.5 mmol) followed by tetrabutylammonium iodide (82mg, 0.22 mmol) and a solution of methanesulfonic acid3,3,3-trifluoro-2-methyl-2-trifluoromethylpropyl ester (6.16 g, 22.5mmol) in DMF (10 mL). Stir at 150° C. overnight, cool the mixture toambient temperature and dilute cautiously with water. Extract threetimes with EtOAc, dry over anhydrous Na₂SO₄, and concentrate in vacuo.Purify by chromatography on silica gel eluting with hexane to give thedesired intermediate as a yellow oil (4.5 g, 62%).1-Bromomethyl-4-(3,3,3-trifluoro-2-meth-yl-2-trifluoromethylpropylthio)benzene:Use a method similar to the Preparation 184, using1-methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio)benzene,to give the title compound.

Preparation 2131-Bromomethyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfinyl)-benzene

1-Methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfinyl)-benzene:To1-methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio)benzene(4.5 g, 14.9 mmol) in acetic acid (15 mL) at ambient temperature, addwith stirring aqueous hydrogen peroxide (15 mL, 30% in water) and stirfor 1 h. Dilute the reaction with water, extract three times with EtOAc,dry over anhydrous Na₂SO₄, and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (9:1) to give thedesired intermediate as a colorless oil (4.125 g, 88%).1-Bromomethyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfinyl)-benzene:To1-methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfinyl)-benzene(4.13 g, 13.0 mmol) in carbon tetrachloride (50 mL) add NBS (2.31 g,13.0 mmol), benzoyl peroxide (314 mg, 1.30 mmol) and stir overnight atreflux. Cool to ambient temperature, dilute with water and extract threetimes with EtOAc. Dry over anhydrous Na₂SO₄ and concentrate in vacuo.Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1)to give the title compound as colorless oil (2.3 g, 55%).

Preparation 214 1-Bromomethyl-4-(2,2-dimethylpropane-1-sulfonyl)benzene

1-(2,2-Dimethyl-propane-1-sulfonyl)-4-methyl-benzene: In a sealed tube,dissolve p-toluenesulfinic acid sodium salt (5.71 g, 32.1 mmol) in DMF(20 mL) and water (10 mL). Add neo-pentyl bromide (6.3 mL, 48 mmol) andtetrabutylammonium iodide (592 mg, 1.60 mmol) and heat the mixture at145° C. overnight. Cool the reaction to ambient temperature, dilute withwater and extract 3 times with EtOAc. Dry over anhydrous Na₂SO₄ andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (9:1) to give the desired intermediate as a colorlessoil (3.3 g, 45%).1-Bromomethyl-4-(2,2-dimethylpropane-1-sulfonyl)benzene: Use a methodsimilar to the Preparation 213 (Step 2), using1-(2,2-dimethylpropane-1-sulfonyl)-4-methyl-benzene, to give the titlecompound.

Preparation 2151-Bromomethyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfonyl)-benzene

1-Methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfonyl)benzene:To1-methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio)benzene(3.47 g, 11.49 mmol) in trifluoroacetic acid (15 mL) at ambienttemperature add with stirring aqueous hydrogen peroxide (15 mL, 30% inwater) and stir for 1 h. After removing trifluoroacetic acid in vacuo,dilute with saturated aqueous NaHCO₃. Extract three times with EtOAc,dry over anhydrous Na₂SO₄, and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (9:1) to give thedesired intermediate as a colorless oil (2.8 g, 74%).1-Bromomethyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfonyl)benzene:Use a method similar to the Preparation 213 (Step 2), using1-methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfonyl)benzene,to give the title compound.

Preparation 2161-Bromomethyl-4-(4′-trifluoromethyl)-phenylsulfonylbenzene

1-Methyl-4-(4-trifluoromethyl)-phenylthio-benzene: Heat a mixture of4-methylbenzenethiol (7.67 g, 61.8 mmol),1-bromo-4-trifluoromethyl-benzene (4.63 g, 20.6 mmol),2,2,6,6-tetramethyl-3,5-heptanedione (379 mg, 2.06 mmol), cesiumcarbonate (20.1 g, 61.8 mmol) and CuCl (102 mg, 1.03 mmol) in NMP (30mL) at 150° C. for 3 h. Cool the mixture to ambient temperature, dilutewith water, extract three times with EtOAc, dry the organic layer overanhydrous Na₂SO₄, and concentrate in vacuo. Recrystallize the residuefrom hexane/EtOAc to give the desired intermediate as a white solid(3.87 g, 70%).1-Bromomethyl-4-(4-trifluoromethyl)-phenylsulfonyl-benzene: Use a methodsimilar to the Preparation 215, using1-methyl-4-(4-trifluoromethyl)-phenylthiobenzene, to give the titlecompound.

Preparation 2171-(4-Bromomethylbenzenesulfonylmethyl)-2,4-difluorobenzene

Use a method similar to the Preparation 214, using 2,4-difluorobenzylbromide, to give the title compound.

Preparation 218 1-Bromomethyl-4-cyclohexylmethanesulfonyl-benzene

Use a method similar to the Preparation 214, using cyclohexylmethylbromide, to give the title compound.

Preparation 219 Methyl 4-bromomethyl-2-fluorobenzoate

Methyl 2-fluoro-4-methyl-benzoate: Mix 1-bromo-2-fluoro-4-methylbenzene(15 g, 79.4 mmol), palladium acetate (712 mg, 3.17 mmol),1,3-bis(diphenylphosphino)-propane (2.94 g, 7.14 mmol), triethylamine(16.1 g, 159 mmol) in methanol (150 mL) and DMF (100 mL). Degas themixture under vacuo and pressurize to 65 psi with carbon monoxide. Stirthe reaction at 110° C. for 2 days. Remove methanol in vacuo, dilute themixture with water, and extract three times with EtOAc. Dry overanhydrous Na₂SO₄ and concentrate in vacuo. Purify by chromatography onsilica gel eluting with hexane/EtOAc (9:1) to give the desiredintermediate as a white solid (7.40 g, 55%). Methyl4-bromomethyl-2-fluoro-benzoate: Use a method similar to the Preparation184, using methyl 2-fluoro-4-methylbenzoate, to give the title compoundas a white solid.

Preparation 220 4-Chloromethyl-N-cyclohexylbenzamide

To 4-chloromethylbenzoyl chloride (1.03 g, 5.47 mmol) in DCM (20 mL) at0° C., add with stirring triethylamine (0.839 mL, 6.02 mmol) followed bycyclohexylamine (0.688 mL, 6.02 mmol), and continue stirring for 15 min.Dilute the reaction mixture with aqueous 1M hydrochloric acid, extractthree times with EtOAc, wash with water and saturated aqueous NaHCO₃.Dry the combined organic extracts over anhydrous Na₂SO₄ and concentratein vacuo to give the title compound as a white solid (1.31 g, 95%).

The compounds of Preparations 221-235 may be prepared essentially asdescribed in Preparation 220 by using 4-chloromethylbenzoyl chloride andthe appropriate amine.

Prep. NH—R Compound 221

4-Chloromethyl-N-(2,2-dimethyl-propyl)-benzamide 222

N-tert-Butyl-4-chloromethyl-benzamide 223

4-Chloromethyl-N-cyclohexylmethyl-benzamide 224

4-Chloromethyl-N-(4-trifluoromethyl-benzyl)-benzamide 225

4-Chloromethyl-N-(2,3,4-trifluoro-benzyl)-benzamide 226

4-Chloromethyl-N-(3,4-difluoro-benzyl)-benzamide 227

4-Chloromethyl-N-(2-fluoro-4-trifluoromethyl-benzyl)-benzamide 228

N-(3,5-Bis-trifluoro-methyl-benzyl)-4-chloromethyl-benzamide 229

4-Chloromethyl-N-(4-fluoro-2-trifluoromethyl-benzyl)-benzamide 230

(S)-4-Chloromethyl-N-(1-cyclohexyl-ethyl)-benzamide 231

(R)-4-Chloromethyl-N-(1-cyclohexyl-ethyl)-benzamide 232

(S)-4-Chloromethyl-N-[1-(4-fluoro-phenyl)-ethyl]-benzamide 233

(R)-4-Chloromethyl-N-[1-(4-fluoro-phenyl)-ethyl]-benzamide 234

(S)-4-Chloromethyl-N-[1-(4-chloro-phenyl)-ethyl]-benzamide 235

(R)-4-Chloromethyl-N-[1-(4-chlorophenyl)-ethyl]-benzamide

Preparation 236 2-(2-Iodoethoxy)propane

Methanesulfonic acid 2-isopropoxyethyl ester: To a stirred solution of2-isopropoxyethanol (2.0 mL, 17.37 mmol) in DCM (100 mL) at ambienttemperature add methanesulfonyl chloride (1.48 mL, 18.08 mmol). Addtriethylamine (2.70 mL, 19.37 mmol) slowly followed by DMAP (catalytic).Continue stirring overnight and concentrate in vacuo. Add diethyl etherand filter. Wash the filtrate with aqueous 1N aqueous HCl, brine, andsaturated aqueous NaHCO₃. Dry over anhydrous MgSO₄ and concentrate invacuo to give the desired intermediate (2.97 g, 94%).2-(2-Iodoethoxy)propane: To a stirred solution of methanesulfonic acid2-isopropoxy-ethyl ester (2.95 g, 16.2 mmol) in acetone (200 mL) atambient temperature add sodium iodide (7.28 g, 19.4 mmol) and continuestirring overnight. Concentrate in vacuo, add diethyl ether and filter,and concentrate in vacuo to give the title compound as a pale yellowliquid (3.12 g, 90%).

Preparation 237 (R)-Toluene-4-sulfonic Acid Tetrahydrofuran-3-yl Ester

To (R)-tetrahydro-furan-3-ol (2.0 g, 22.7 mmol), triethylamine (3.8 mL,27.3 mmol), DMAP (277 mg, 2.26 mmol), and silver oxide (5.26 g, 22.7mmol) in dry DCM (30 mL) at 0° C. under nitrogen, add portion wise withstirring p-toluenesulfonyl chloride (4.76 g, 25.0 mmol). Warm to ambienttemperature overnight, filter from silver salts, and concentrate invacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc(7:1) to give the title compound as a clear liquid (4.7 g, 85%).

Preparation 238 (S)-Toluene-4-sulfonic Acid Tetrahydrofuran-3-yl Ester

Use a method similar to the Preparation 237, using(S)-tetrahydro-furan-3-ol, to give the title compound as a clear liquid.

Preparation 239 2-(2-Bromoethyl)-pyridine Hydrobromide

Use a method similar to the bromination procedure described inPreparation 186 (Step 2), using 2-pyridineethanol, to give the titlecompound. Recrystallize from 2-propanol to give a light brown solid.

Preparation 240 5-(3-Bromopropyl)-3-tert-butyl-[1,2,4]oxadiazole

4-Bromobutyric acid vinyl ester: To 4-bromobutyric acid (1.0 g, 6.0mmol) in vinyl acetate (54 mL) add with stirring palladium(II) acetate(188 mg, 0.84 mmol) and continue stirring overnight at ambienttemperature. Filter and concentrate in vacuo to provide the crudedesired intermediate.5-(3-Bromopropyl)-3-tert-butyl[1,2,4]oxadiazole: Use a method similar tothe Preparation 178, using 4-bromobutyric acid vinyl ester, to give thetitle compound.

Preparation 241 1-Bromomethyl-2-fluoro-4-phenoxybenzene

2-(4-Bromo-2-fluoro-benzyloxy)-tetrahydro-pyran: Mix under nitrogenatmosphere 4-bromo-2-fluorobenzyl alcohol, (4.1 g, 20 mmol),dihydropyran (2 g, 24 mmol), p-toluenesulfonic acid monohydrate (100 mg,0.52 mmol), and anhydrous DCM (70 mL). Stir for 16 h at ambienttemperature. Dilute with DCM, wash sequentially with saturated aqueousNaHCO₃ then brine. Separate the organic layer, dry over Na₂SO₄ andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate as aclear oil (4.36 g, 75%). MS (ES+) m/z: 312 (M+Na)⁺.2-(2-Fluoro-4-phenoxy-benzyloxy)-tetrahydro-pyran: Mix under argonatmosphere 2-(4-bromo-2-fluorobenzyloxy)-tetrahydropyran (2.9 g, 10mmol), phenol (1.9 g, 20 mmol), 2,2,6,6-tetramethylheptane-3,5-dione(184.3 mg, 1.0 mmol), cesium carbonate (6.5 g, 20 mmol) and anhydrousNMP (20 mL). Degas the flask and fill with argon. Add copper(I) chloride(495 mg, 5 mmol) quickly. Degas the flask three times then fill withargon. Heat at 120° C. for 3 h. Cool to ambient temperature. Dilute withEtOAc and filter. Concentrate in vacuo and purify by chromatography onsilica gel to obtain the desired intermediate (2.05 g, 68%). MS (ES+)m/z: 325 (M+Na)⁺.(2-Fluoro-4-phenoxy-phenyl)-methanol: Mix under nitrogen atmosphere2-(2-fluoro-4-phenoxy-benzyloxy)-tetrahydro-pyran (2.05 g, 6.8 mmol),methanol (60 mL) and p-toluenesulfonic acid monohydrate (260 mg, 1.35mmol). Stir at ambient temperature for 16 h. Dilute with EtOAc. Washwith saturated aqueous NaHCO₃. Separate the organic layer, dry overNa₂SO₄ and concentrate in vacuo to give the desired intermediate (1.41g, 95%). MS (ES+) m/z: 201 (M-OH)⁺.1-Bromomethyl-2-fluoro-4-phenoxy-benzene: Dissolve under nitrogenatmosphere (2-fluoro-4-phenoxyphenyl)-methanol (1.41 g, 6.5 mmol) inanhydrous THF (60 mL). Cool to 0° C. in an ice bath. Add phosphoroustribromide (2.11 g, 7.8 mmol). Stir at cold for 1 h, then remove the icebath and stir at ambient temperature for 16 h. Quench the reaction withsaturated aqueous NaHCO₃. Extract aqueous phase three times with EtOAc.Combine organic fractions, wash with brine, dry over Na₂SO₄ andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (9:1). Evaporate the solvent to obtain the titlecompound (1.31 g, 72%).

Preparation 2423-tert-Butoxycarbonyl-7-chloro-6-(4-hydroxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

3-tert-Butoxycarbonyl-6-(4-carboxy-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine:To a solution of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.0 g, 2.6 mmol) in methanol (15 mL) under nitrogen, add with stirringpotassium hydroxide (4.5 g, 80.3 mmol) at ambient temperature. Heat at55-60° C. for 2 h, cool to ambient temperature, and add methyl4-bromomethylbenzoate (1.2 g, 5.2 mmol). TLC after 20 min showsformation of product; however, after 4 h at ambient temperature both TLCand LC/MS indicate complete hydrolysis of the ester and the carbamate.Dilute with saturated aqueous NH₄Cl, extract three times with EtOAc, dryover anhydrous MgSO₄, and concentrate in vacuo. Dissolve the crudematerial in THF (10 mL), treat with di-tert-butyl-dicarbonate (2 equiv)and saturated aqueous NaHCO₃ (10 mL), and stir overnight. Extract threetimes with EtOAc, dry over anhydrous MgSO₄ and concentrate in vacuo togive the desired intermediate as an oil that was used withoutpurification [2.32 g, 50% purity with (Boc)₂O]. MS (ES+) m/z 348(M+H-Boc)⁺.3-tert-Butoxycarbonyl-7-chloro-6-(4-hydroxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:To a solution of3-tert-butoxycarbonyl-6-(4-carboxybenzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.85 g, 50% purity, 2.06 mmol) in anhydrous THF (40 mL) under nitrogen,add with stirring 1M borane in THF (4.2 mL) at 0° C. Warm to ambienttemperature and stir 2-3 h. Quench by the careful addition of water (3mL), dilute with saturated aqueous NaHCO₃, extract three times withethyl ether, dry over anhydrous MgSO₄, and concentrate in vacuo. Purifyby chromatography on silica gel eluting with hexane/EtOAc (5:1) toprovide the title compound as a white solid (485 mg, 54%).

Preparation 2433-tert-Butoxycarbonyl-7-chloro-6-(4-methanesulfonylmethylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

3-tert-Butoxycarbonyl-7-chloro-6-(4-methanesulfonyloxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:To a stirred solution of3-tert-butoxycarbonyl-7-chloro-6-(4-hydroxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(170 mg, 0.391 mmol) in anhydrous DCM under nitrogen, addmethanesulfonyl chloride (33 μL, 0.426 mmol) and triethylamine (61 μL,0.44 mmol) and continue stirring for 2 h. Dilute with water (5 mL) andextract three times with DCM. Wash the combined organic extracts withbrine, dry over anhydrous Na₂SO₄, and concentrate in vacuo to obtain thedesired intermediate that was used without purification.3-tert-Butoxycarbonyl-6-(4-bromomethyl-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve the crude3-tert-butoxycarbonyl-7-chloro-6-(4-methanesulfonyloxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepinein anhydrous acetone (3 mL), treat with anhydrous lithium bromide (335mg, 3.89 mmol) and continue stirring overnight. Add water, extract thereaction mixture three times with ethyl ether, wash with brine, dry overanhydrous MgSO₄, and concentrate in vacuo to obtain the desiredintermediate that was used without purification.3-tert-Butoxycarbonyl-7-chloro-6-(4-methanesulfonylmethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:To the crude3-tert-butoxycarbonyl-6-(4-bromomethyl-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepinein anhydrous DMF (1 mL) under nitrogen, add with string sodiummethanesulfinate (400 mg, 3.9 mmol), and continue stirring for 30 min atambient temperature followed by 2 h at 40° C. Add water, extract threetimes with EtOAc, wash with brine, dry over anhydrous MgSO₄, andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (3:1) to give a clear oil that solidifies on standingto a white solid (118 mg, 61%).

Preparation 2446-(4-Bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

1-Bromo-4-bromomethyl-2-fluorobenzene: Use a method similar to thePreparation 184, using 4-bromo-3-fluorotoluene, to give the desiredintermediate as a white solid.6-(4-Bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Use a method similar to the Preparation 177, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 1-bromo-4-bromomethyl-2-fluorobenzene, to give the title compound asa white solid.

Preparation 245(±)-3-tert-Butoxycarbonyl-7-chloro-6-(1-methoxycarbonyl-1-phenyl-methyllthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

(±)-3-tert-Butoxycarbonyl-6-(1-carboxy-1-phenyl-methyllthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine:To a solution of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.23 g, 3.2 mmol) in methanol (20 mL) under nitrogen, add with stirringpotassium hydroxide (5.36 g, 95.5 mmol) at ambient temperature. Heat at55-60° C. for 2 h, cool to ambient temperature, and add methylα-bromophenylacetate (600 μL, 3.81 mmol). After 30 min, dilute withsaturated aqueous NH₄Cl, extract three times with EtOAc, dry overanhydrous MgSO₄, and concentrate in vacuo. Dissolve the crude materialin THF (10 mL), treat with di-tert-butyl-dicarbonate (2 equiv) andsaturated aqueous NaHCO₃ (10 mL), and stir overnight. Extract threetimes with EtOAc, dry over anhydrous MgSO₄ and concentrate in vacuo togive the desired intermediate as an oil that is used withoutpurification (1.1 g, 77%).(±)-3-tert-Butoxycarbonyl-6-(1-methoxycarbonyl-1-phenyl-methyllthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Treat a solution of3-tert-butoxycarbonyl-6-(1-carboxy-1-phenyl-methylthio)-7-chloro-2,3,4,5-tetrahydrobenzo[d]azepine(200 mg, 0.447 mmol) in anhydrous DMF (2 mL) with methyl iodide (317 mg,2.237 mmol) and potassium carbonate (310 mg, 2.237 mmol) for 1.5 h atambient temperature. Add water and extract the aqueous phase three timeswith EtOAc. Dry the organic phase over MgSO₄ and concentrate to obtainthe title compound that was used without purification.

Preparation 2466-(3-Bromo-4-chloro-benzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

2-Bromo-4-bromomethyl-1-chloro-benzene: Use a method similar to thePreparation 184, using 3-bromo-4-chlorotoluene, to give the desiredintermediate.6-(3-Bromo-4-chloro-benzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Use a method similar to the Preparation 177, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylsulfanyl-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2-bromo-4-bromomethyl-1-chloro-benzene, to give the title compound.

Preparation 2473-tert-Butoxycarbonyl-6-(5-carboxy-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

3-tert-Butoxycarbonyl-4-chloro-6-(5-methoxycarbonyl-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve3-tert-butoxycarbonyl-6-(5-bromopyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(2.13 g, 4.40 mmol), palladium acetate (35 mg, 0.156 mmol),1,1′-bis(diphenylphosphino)ferrocene (150 mg, 0.271 mmol) andtriethylamine (1.30 mL) in methanol (10 mL) and DMF (5 mL). Degas andthen heat under a balloon filled with carbon monoxide at 75° C. for 10h. Remove methanol in vacuo, and dilute the mixture with water. Extractthree times with EtOAc, dry over anhydrous Na₂SO₄, and concentrated invacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc(7:1) to give the desired intermediate as a clear oil (1.86 g, 91%). MS(APCI+) m/z 463 (M+H)⁺, 363 (M+H-Boc)⁺.3-tert-Butoxycarbonyl-6-(5-carboxy-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve3-tert-butoxycarbonyl-7-chloro-6-(5-methoxycarbonyl-pyridin-2-ylmethylthio)-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.86 g, 4.03 mmol) in methanol (25 mL). Add 1M aqueous lithiumhydroxide (12 mL) and stir at ambient temperature overnight. Removemethanol in vacuo, and dilute the mixture with cold 0.5M aqueous HCl topH 4. Add brine and extract three times with EtOAc. Dry over anhydrousNa₂SO₄, and concentrate in vacuo to give the title compound as anoff-white solid (1.78 g, 95%). MS (APCI+) m/z 449 (M+H)⁺, 349(M+H-Boc)⁺.

Preparation 2486-(4-Bromo-thiophen-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

3-Bromo-5-bromomethyl-thiophene: Use the bromination procedure describedin Preparation 211 (Step 2), using (3-bromothiophen-2-yl)methanol(Synthesis 1983, 1, 73-75), to give the desired intermediate as a lightbrown liquid.6-(4-Bromo-thiophen-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Use a method similar to the Preparation 177, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[a]azepineand 3-bromo-5-bromomethyl-thiophene, to give the title compound as agum.

EXAMPLE 3157-Chloro-6-(2-isopropoxyethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To a 4:1 mixture of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.52 mmol) in methanol (5 mL) under nitrogen, add potassiumhydroxide (0.9 g, 16.1 mmol) at ambient temperature. When the mixturebecomes homogenous, heat at 55-60° C. for 2-3 h, until TLC shows thedisappearance of starting material. Cool to ambient temperature, addaqueous saturated ammonium chloride, extract three times with diethylether, dry over anhydrous MgSO₄, and concentrate in vacuo. Dissolve thecrude3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepinein anhydrous THF (5 mL) under nitrogen and add with stirring 1.0 Mpotassium t-butoxide in THF (1.0 mL) at ambient temperature. After 10min, add 2-(2-iodoethoxy)propane (223 mg, 1.04 mmol), and allow thereaction to continue overnight. Dilute with aqueous saturated ammoniumchloride, extract the mixture three times with diethyl ether, dry overanhydrous MgSO₄, and concentrate in vacuo. Purify by chromatography onsilica gel eluting with hexane/EtOAc (12:1) to provide3-tert-butoxycarbonyl-7-chloro-6-(2-isopropoxy-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a clear oil (127 mg, 63%). Use a method similar to the GeneralProcedure 1-4 to give the title compound as a white solid. MS (ES+) m/z:300 (M+H)⁺.

EXAMPLE 316(±)-7-Chloro-6-(1-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 7, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand (±)-2-(1-bromoethyl)-pyridine to give, after deprotection by amethod similar to the General Procedure 1-4, the title compound as awhite solid. MS (APCI+) m/z: 319 (M+H)⁺.

EXAMPLE 317(−)-7-Chloro-6-(1-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Separate the enantiomers of(±)-7-chloro-6-(1-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineby chiral normal phase chromatography (Chiralpak AD 8×30 cm column,eluting with 0.2% DMEA in methanol). Take the second eluting isomer andpurify by chromatography on silica gel eluting with DCM/2M ammonia inmethanol (100:1 to 80:20).

Use the General Procedure 2-1 to give the title compound as a whitesolid (4.27 g, 33%). MS (ES+) m/z: 319 (M+H)⁺; ee=99.4%; [α]²⁰ _(D)−179° (c 0.5, CH₃OH).

EXAMPLE 318(−)-7-Chloro-6-(1-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 7, except that thealkylation is conducted at 0° C., to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2;3,4,5-tetrahydro-1H-benzo[d]azepinewith (R)-(−)-1-(2-pyridinyl)ethanol methanesulfonate ester. Use a methodsimilar to the General Procedure 1-4 to give the title compound as awhite solid. MS (APCI+) m/z: 319 (M+H)⁺; ee=98.6% [Chiral HPLC:Chiralpak AD-H 0.46×15 cm column, eluting with 15:85 ethanol/heptane].

EXAMPLE 319(±)-7-Chloro-6-[1-(6-methylpyridin-2-yl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 315, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand (±)-2-(1-chloroethyl)-6-methylpyridine hydrochloride to give, afterdeprotection by a method similar to the General Procedure 1-4, the titlecompound as a tan solid. MS (ES+) m/z: 333 (M+H)⁺.

EXAMPLE 3207-Chloro-6-[1-(6-methylpyridin-2-yl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride, Isomer 1

Use a method similar to the Preparation 177, except that the alkylationis conducted at 0° C., to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith (R)-methanesulfonic acid 1-(6-methyl-pyridin-2-yl)-ethyl ester. Usea method similar to the General Procedure 1-5, basic workup, and amethod similar to the General Procedure 2-2 to give the title compoundas a white solid. MS (APCI+) m/z: 333 (M+H)⁺; ee >97%, t_(R)=6.53 min.(Chiral HPLC: Chiralpak OJ 120 Å 4.6×250 mm, 45° C.; eluent: 20%isopropanol with 0.05% triethylamine in SFC, flow rate 2 mL/min, LTVdetector at 234 nm).

EXAMPLE 321(±)-7-Chloro-6-[1-(3-methylpyridin-2-yl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Preparation 177 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith (±)-2-(1-bromoethyl)-3-methyl-pyridine. Use a method similar to theGeneral Procedure 1-5, basic workup, and a method similar to the GeneralProcedure 2-2 to give the title compound as a white solid. MS (APCI+)m/z: 333 (M+H)⁺.

EXAMPLE 322(−)-7-Chloro-6-[1-(3-methylpyridin-2-yl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Separate the enantiomers of(±)-7-chloro-[1-(3-methyl-pyridin-2-yl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineby chiral normal phase chromatography (Chiralpak AD 8×30 cm column,eluting with 85:15 heptane:0.2% DMEA in ethanol). Take the secondeluting isomer and purify by SCX column chromatography.

Use the General Procedure 2-2 to give the title compound as a whitesolid (60 mg, 43%). MS (ES+) m/z: 333 (M+H)⁺; [α]²⁰ _(D) −232° (c 0.5,CH₃OH).

EXAMPLE 323(±)-7-Chloro-6-(2,2,2-trifluoro-1-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Preparation 177 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith (±)-2-[1-methanesulfonyloxy-(2,2,2-trifluoroethyl)]-pyridine. Use amethod similar to the General Procedure 1-5, basic workup, and a methodsimilar to the General Procedure 2-2 to give the title compound as awhite solid. MS (APCI+) m/z: 373 (M+H)⁺.

EXAMPLE 324(±)-7-Chloro-6-(1-pyridin-2-yl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use method similar to the Preparation 177 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith (±)-2-(1-bromopropyl)pyridine. Use a method similar to the GeneralProcedure 1-5, basic workup, and a method similar to the GeneralProcedure 2-2 to give the title compound as a white solid. MS (APCI+)m/z: 333 (M+H)⁺.

EXAMPLE 325(±)-7-Chloro-6-[1-(pyridazin-3-yl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineOxalate

Dissolve (±)-1-pyridazin-3-yl-ethanol (38 mg, 0.31 mmol) in thionylchloride (0.14 mL) at 0° C. and stir for 1 h at ambient temperature.Evaporate the mixture, add toluene and evaporate again. Treat thisresidue with the thiolate prepared from7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine-3-carboxylicacid tert-butyl ether (0.1 g, 0.25 mmol) according to the GeneralProcedure 7 in the presence of potassium carbonate (0.3 g, 2.25 mmol) inDMF (3 mL) at 80° C. for 16 h.

Use a method similar to the General Procedure 1-5, basic work-up, and amethod similar to the General Procedure 2-5 to give the title compound(38 mg, 37%). HRMS calcd for C₁₆H₁₉ClN₃S 320.0988, found 320.0970.

EXAMPLE 326(+)-7-Chloro-6-[1-(pyridazin-3-yl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineOxalate

Dissolve (±)-1-pyridazin-3-yl-ethanol (0.29 g, 2.35 mmol) in thionylchloride (1.0 mL) at 0° C. and stir for 1 h at ambient temperature.Evaporate the mixture, add toluene and evaporate again. Treat thisresidue with the thiolate prepared from7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine-3-carboxylicacid tert-butyl ether (0.72 g, 1.88 mmol) according to the GeneralProcedure 7 in the presence of potassium carbonate (2.60 g, 18.8 mmol)and tetrabutylammonium iodide (7 mg, 0.02 mmol) in DMF (20 mL) at 80° C.for 28 h. Separate the enantiomers by preparative HPLC (Waters SymmetryC18 4.6×150 mm 3.5 micron column, 1 mL/min of 90:10 to 50:50:0.1% TFA inwater:ACN over 25 min. Detector is at 254 nm) to obtain3-tert-butoxycarbonyl-7-chloro-6-[1-(pyridazin-3-yl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine,isomer 1.

Use a method similar to the General Procedure 1-5, basic work-up, and amethod similar to the General Procedure 2-5 to give the title compound(56 mg, 7%). HPLC t_(R)=3.0 min (Chiralpak AD-H 4.6×150 mm, 3 microncolumn, 1.0 mL/min of 99.8:0.2 methanol/dimethylethylamine isocratic;detector at 225 nm); HRMS calc'd for C₁₆H₁₉ClN₃S 320.0988, found320.1001. [α]²⁰ _(D) +160° (c 0.5, CH₃OH).

EXAMPLE 3277-Chloro-6-(pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

React 3-chloromethyl-pyridazine (prepared as described in WO 99/54333,WO 98/49166) (1.8 g, 11.0 mmol) with3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(2.2 g, 5.7 mmol) according to the General Procedure 7 in the presenceof tetrabutylammonium iodide (0.1 g, 0.27 mmol) at ambient temperaturefor 3 h.

Use a method similar to the General Procedure 14 to give the titlecompound as a tan powder (1.9 g, 98%): HRMS calcd for C₁₅H₁₆ClN₃S306.0832, found 306.0829.

EXAMPLE 3287-Chloro-6-(6-chloro-pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Preparation 177, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 3-bromomethyl-6-chloropyridazine to give3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro)-1H-benzo[d]azepine.Use a method similar to the General Procedure 14 to give the titlecompound as an off-white powder. MS (APCI+) m/z: 340 (M+H)⁺.

EXAMPLE 3297-Chloro-6-[6-(2,2-dimethylpropoxy)-pyridazin-3-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To a stirred solution of neopentyl alcohol (105 mg, 1.19 mm ol) in THF(5 mL) at ambient temperature add sodium hydride (31 mg, 95%, 1.19 mmol)and continue stirring for 3 h at ambient temperature. Add a solution of3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(315 mg, 0.59 mmol) in THF (1 mL) and continue stirring overnight atambient temperature and then at 60° C. for 1 h. Dilute with water,extract the reaction mixture three times with EtOAc, dry over anhydrousNa₂SO₄, and concentrate in vacuo. Purify by chromatography on silica geleluting with hexane/EtOAc (6:1) to give3-tert-butoxycarbonyl-7-chloro-6-[6-(2,2-dimethyl-propoxy)-pyridazin-3-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a clear oil (81 mg, 28%). MS (APCI+) m/z: 492 (M+H)⁺, 392 (M+H-Boc)⁺.Use a method similar to the General Procedure 1-4 to give the titlecompound as a white powder. MS (APCI+) m/z: 392 (M+H)⁺, m/z: 322(M+H—C₅H₁₁)⁺.

EXAMPLE 3307-Chloro-6-(thiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To a 4:1 mixture of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo[d]azepine(108 mg, 0.281 mmol) in methanol (3 ml), add potassium hydroxide pellets(504 mg, 9.0 mmol) and heat the mixture 2 h at 50° C. Cool the reactionto ambient temperature, add 2-chloromethylthiophene (186 μL, 1.406mmol), and continue stirring for 30 min. Dilute with EtOAc and water.Separate the layers and extract the aqueous layer three times withEtOAc, dry over anhydrous Na₂SO₄, and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (19:1) to give3-tert-butoxycarbonyl-7-chloro-6-(thiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-benzo[d]azepineas a colorless oil (36 mg, 31%).

Use a method similar to the General Procedure 1-5, using3-tert-butoxycarbonyl-7-chloro-6-(thiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-benzo[d]azepineto give, after basic workup and a method similar to the GeneralProcedure 2-2, the title compound as a white solid. MS (ES+) m/z: 310(M+H)⁺.

EXAMPLE 331(±)-7-Chloro-6-(3-cyanothiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

Use a method similar to the Preparation 177, using3-tert-butoxycarbonyl-7-chloro-6dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and(±)-2-(1-chloroethyl)-3-cyanothiophene to give, after deprotection usinga method similar to the General Procedure 1-5, the title compound as awhite solid. MS (APCI+) m/z: 349 (M+H)⁺.

EXAMPLE 3327-Chloro-6-(5-methylisoxazol-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To a 4:1 mixture of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.521 mmol) in methanol (3.3 mL) under nitrogen add potassiumhydroxide (0.9 g, 16.1 mmol) at ambient temperature. When the mixturebecomes homogenous, heat at 55-60° C. for 2-3 h, until TLC shows thedisappearance of starting material. Cool to ambient temperature, add3-(chloromethyl)-5-methylisoxazole (82 mg, 0.62 mmol) and continuestirring for 30 min. Add aqueous saturated ammonium chloride, extractthe mixture three times with diethyl ether, dry over anhydrous MgSO₄,and concentrate in vacuo. Treat a solution of the crude material soobtained in DCM (2 mL) with 2M hydrogen chloride in ether (excess) andcontinue stirring until TLC shows consumption of the starting material.Concentrate in vacuo, purify by preparative TLC eluting with 19:1DCM/saturated ammonia in methanol, and convert to the hydrochloride byfollowing a method similar to the General Procedure 2-2 to give thetitle compound as a white solid. MS (APCI+) m/z: 309 (M+H)⁺.

EXAMPLE 3337,9-Dichloro-6-(5-methylisoxazol-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Obtain the free base of the title compound as a minor product fromExample 332, after preparative TLC eluting with 19:1 DCM/saturatedammonia in methanol. Use a method similar to the General Procedure 2-2to give the title compound as a white solid. MS (APCI+) m/z: 343 (M+H)⁺.

EXAMPLE 3347-Chloro-6-(2-methylthiazol-4-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 332, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4-chloromethyl-2-methylthiazole hydrochloride to give, afterdeprotection by the General Procedure 1-4, the title compound as a whitesolid. MS (APCI+) m/z: 325 (M+H)⁺.

EXAMPLE 3356-(4-Bromothiophen-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 14, using6-(4-bromothiophen-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give the title compound as a white solid. MS (APCI+) m/z: 390 (M+H)⁺.

EXAMPLE 3367-Chloro-6-(4-cyanothiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Degas a stirred solution of6-(4-bromothiophen-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(183 mg, 0.37 mmol), zinc cyanide (50 mg, 0.42 mmol) andtetrakistriphenylphosphine palladium(0) (30 mg, 0.026 mmol) in dry DMF.Purge with dry nitrogen, and heat at 120° C. for 6 h. Dilute with water,extract three times with EtOAc, dry over anhydrous MgSO₄ and concentratein vacuo. Purify by chromatography on silica gel eluting withhexane/EtOAc (10:1) to give3-tert-butoxycarbonyl-7-chloro-6-(4-cyanothiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (85 mg, 52%). MS (APCI+) m/z: 335 (M+H-Boc)⁺. Use a methodsimilar to the General Procedure 1-4 to give the title compound as awhite solid. MS (APCI+) m/z: 335 (M+H)⁺.

EXAMPLE 3377-Chloro-6-([1,2,4]-oxadiazol-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Preparation 177, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 3-chloromethyl-1,2,4-oxadiazole to give, after deprotection using amethod similar to the General Procedure 1-4, the title compound as awhite solid. MS (ES+) m/z 296 (M+H)⁺.

Examples 338-343 may be prepared essentially as described in Example 337using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriately substituted 5-chloromethyl-1,2,4-oxadiazole or 4chloromethyl-thiazole. MS (ES+) data are included in the Table below.

MS Ex. SR Compound (ES+) m/z 338

7-Chloro-6-(3-methyl-[1,2,4]oxadiazol-5-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride310(M + H)⁺ 339

6-(3-tert-Butyl-[1,2,4]oxadiazol-5-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride352(M + H)⁺ 340

7-Chloro-6-(3-propyl-[1,2,4]oxadiazol-5-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride338(M + H)⁺ 341

7-Chloro-6-[3-(4-chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride406(M + H)⁺ 342

7-Chloro-6-(3-pyridin-2-yl-[1,2,4]oxadiazol-5-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride373(M + H)⁺ 343

7-Chloro-6-[2-(4-trifluoromethyl-phenyl)-thiazol-4-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride455(M + H)⁺

EXAMPLE 3447-Chloro-6-(pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Using a method similar to the General Procedure 7, react3-tert-butoxycarbonyl-7-chloro-6-dimethylaminocarbonylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(8 g, 20.8 mmol) with 2-picolyl chloride hydrochloride (3.41 g, 20.8mmol). Dilute the reaction mixture with diethyl ether and filter theprecipitate. Concentrate the filtrate in vacuo, dissolve the residue indiethyl ether (100 mL) and add 1N aqueous HCl (100 mL). Stir the mixturefor 16 h at ambient temperature. Separate, wash the aqueous layer withdiethyl ether, adjust the pH of the aqueous layer to 12 with sodiumhydroxide and extract with diethyl ether. Dry over Na₂SO₄ andconcentrate in vacuo to give the free base of the title compound. Usethe General Procedure 2-2 to give the title compound as a white solid(4.91 g, 78%). MS (ES+) m/z: 305 (M+H)⁺.

EXAMPLE 3457-Chloro-6-(pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Dissolve3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1 equiv.) in methanol (0.1-0.4 M) and add potassium hydroxide (8-20equiv.). Stir at 60° C. for 4-24 h. Cool the reaction mixture in an icebath, add picolyl chloride hydrochloride (1-3 equiv.) and stir themixture at ambient temperature for 16-24 h. Add a volume of tolueneapproximately equal to the volume of the reaction mixture andconcentrate the resulting mixture to approximately ½ the resulting totalvolume and repeat this process once more. Add water until all solidsdissolve and separate the layers. Dry the organic layer over Na₂SO₄ andfilter. Heat the solution (containing about 0.25-0.40 M of free base ofthe title compound) to 50-75° C. and then optionally seed withpreviously formed crystals of the title compound. Add succinic acid(1-1.3 equivalents) in isopropyl alcohol (0.25-0.40M solution) to thesolution over 545 min. Cool the solution to 20-25° C. over 1-3 h andfilter, rinsing with a solution of toluene/isopropyl alcohol (1:1). Drythe resulting solid under vacuum at 50-70° C./5 Torr to give the titlecompound as a white solid, mp 159-160° C. Anal. Calc'd forC₂₀H₂₃ClN₂O₄S: C, 56.80; H, 5.48; N, 6.62. Found: C, 56.56; H, 5.41; N,6.57.

EXAMPLE 3467,9-Dichloro-6-(pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Obtain as minor product from the reaction of the 4:1 mixture of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo[d]azepinewith 2-bromomethylpyridine hydrobromide, using a method similar to theGeneral Procedure 7. Treat a solution of the crude mixture in DCM with4M hydrogen chloride in dioxane (excess) overnight Concentrate in vacuoand purify by preparative TLC eluting with 19:1 DCM/saturated ammonia inmethanol. Use a method similar to the General Procedure 2-2 to give thetitle compound as an off-white solid. MS (APCI+) m/z: 339 (M+H)⁺.

EXAMPLE 3477-Chloro-6-(2-fluorobenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To a mixture of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo[d]azepine(102 mg, 0.267 mmol) in methanol (2 ml), add potassium hydroxide pellets(450 mg, 8.02 mmol) and heat the mixture 3 h at 60° C. Cool to ambienttemperature, add aqueous saturated ammonium chloride solution, extractthree times with EtOAc, dry over anhydrous Na₂SO₄, and concentrate invacuo. Dissolve the crude thiophenol thus obtained in dry DCM (2 mL)under nitrogen, and add DBU (80 □L, 0.54 mmol) and 2-fluorobenzylbromide (65 □L, 0.54 mmol) with stirring. Stir overnight at ambienttemperature, dilute with water, extract three times with EtOAc, dry overanhydrous Na₂SO₄, and concentrate in vacuo. Purify by chromatography onsilica gel eluting with hexane/EtOAc (9:1) to give3-tert-butoxycarbonyl-7-chloro-6-(2-fluorobenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (31 mg, 25%). Use a method similar to the GeneralProcedure 1-4 to give the title compound as a white solid. MS (ES+) m/z:322 (M+H)⁺.

EXAMPLE 3487-Chloro-6-(pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 347, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 3-(bromomethyl)pyridine hydrobromide to give, after deprotection bya method similar to the General Procedure 1-4, the title compound as awhite solid. MS (ES+) m/z: 305 (M+H)⁺.

EXAMPLE 3497-Chloro-6-(5-fluoropyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Dissolve3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(527 mg, 1.4 mmol) and potassium hydroxide (1.1 g, 20.5 mmol) inmethanol (10 mL) and heat the solution to reflux for 2 h. Cool thereaction mixture to ambient temperature and remove the solvent in vacuo.Slurry the residue with EtOAc (50 ml), and wash the slurry with asaturated NH₄Cl. Collect and dry the organic phase over Na₂SO₄, removethe solvent under reduced pressure to obtain the intermediate thiophenolas an oil. Dissolve the oil in DMSO (10 ml), add triethylamine (1.1 ml,8.2 mmol) and methanesulfonic acid 5-fluoro-pyridin-2-ylmethyl ester(500 mg, 2.4 mmol). Heat the reaction mixture to 60° C. for 1 h. Monitorthe reaction by HPLC and TLC. Cool the reaction to ambient temperature,add 1:1 hexane/EtOAc (80 ml) and wash the organic layer with a 5% NaCl(3×30 ml). Collect the organic layer, concentrate, and purify bychromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) toobtain3-tert-butoxycarbonyl-7-chloro-6-(5-fluoro-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(519 mg, 89%). MS (ES+) m/z: 423 (M+H)⁺.

Use the General Procedure 1-4 to deprotect3-tert-butoxycarbonyl-7-chloro-6-(5-fluoro-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(510 mg, 1.2 mmol). Purify by SCX chromatography followed bychromatography on silica gel eluting with DCM/2M ammonia in methanol(99:1 to 90:10). Use the General Procedure 2-1 to give the titlecompound (370 mg, 70%). MS (ES+) m/z: 323 (M+H)⁺.

EXAMPLE 3507-Chloro-6-(6-chloropyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Preparation 177, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2-bromomethyl-6-chloropyridine hydrochloride to give, afterdeprotection by a method similar to the General Procedure 1-4, the titlecompound as an off-white solid. MS (APCI+) m/z: 339 (M+H)⁺.

Examples 351-360 may be prepared essentially as described in Example 350by using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriately substituted chloromethylpyridine,bromomethylpyridine or chloromethylquinoline. MS (ES+) data are includedin the Table below.

MS (ES+ Ex. SR Compound or APCI+) 351

7-Chloro-6-(6-chloro-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride339(M + H)⁺ 352

6-(5-Bromo-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride385(M + H)⁺ 353

6-(3-Bromo-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride385(M + H)⁺ 354

6-(6-Bromo-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochioride385(M + H)⁺ 355

7-Chloro-6-(3-methyl-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride319(M + H)⁺ 356

7-Chloro-6-(5-cyano-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride330(M + H)⁺ 357

7-Chloro-6-(6-cyano-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride330(M + H)⁺ 358

7-Chloro-6-(6-trifluoromethyl-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride373(M + H)⁺ 359

7-Chloro-6-(3-trifluoro-methyl-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride373(M + H)⁺ 360

7-Chloro-6-(quinolin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride355(M + H)⁺

EXAMPLE 3617-Chloro-6-(3-methoxypyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 315, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2-chloromethyl-3-methoxypyridine to give, after deprotection by amethod similar to the General Procedure 1-4, the title compound as awhite solid (71 mg). MS (APCI+) m/z: 335 (M+H)⁺.

EXAMPLE 3627-Chloro-6-(6-methoxypyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 330, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2-chloromethyl-6-methoxypyridine hydrochloride to give, afterdeprotection by a method similar to the General Procedure 14, the titlecompound as a white solid (120 mg). MS (APCI+) m/z: 335 (M+H)⁺.

EXAMPLE 3636-(5-Butylpyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 315, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 5-butyl-2-chloromethylpyridine hydrochloride to give the titlecompound as a white solid. MS (APCI+) m/z: 330 (M+H)⁺.

EXAMPLE 3647-Chloro-6-[5-(3-methylbutyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To6-(5-bromo-pyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(219 mg, 0.452 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (18 mg, 0.022 mmol) under dry nitrogen add withstirring a solution of 0.5M 3-methylbutylzinc bromide in TIE (4.6 mL,2.3 mmol). Degas, purge with dry nitrogen, and stir overnight at ambienttemperature. Dilute with EtOAc, wash with water, dry over anhydrousMgSO₄ and concentrate in vacuo. Purify by chromatography on silica geleluting with hexane/EtOAc (5:1) to give3-tert-butoxycarbonyl-7-chloro-6-[5-(3-methyl-butyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (160 mg, 75%). MS (APCI+) m/z: 475 (M+H)⁺. Use a methodsimilar to the General Procedure 1-4 to give the title compound as a tansolid. MS (APCI+) m/z: 375 (M+M)⁺.

EXAMPLE 3657-Chloro-6-[5-(2,2-dimethylpropyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To a stirred solution of 1.0 M neopentyl magnesium chloride in diethylether (50 mL, 50 mmol) at −78° C. under nitrogen, add via syringe asolution of 0.5 M zinc chloride in THF (100 mL, 50 mmol). Warm graduallyto ambient temperature and transfer via syringe of this solution (25 mL,˜8.33 mmol) to a stirred solution of3-tert-butoxycarbonyl-6-(5-bromo-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(300 mg, 0.62 mmol) in THF (2 mL) at ambient temperature. Adddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (50 mg, 0.061 mmol) and heat at 65° C. for 6 h.Cool to ambient temperature, dilute with EtOAc, wash with water, dryover anhydrous MgSO₄ and concentrate in vacuo. Purify by chromatographyon silica gel eluting with hexane/EtOAc (6:1) to give3-tert-butoxycarbonyl-7-chloro-6-[5-(2,2-dimethyl-propyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (69 mg, 24%). MS (APCI+) m/z: 501 (M+H)⁺. Use a method similarto the General Procedure 1-4 to give the title compound as a whitepowder. MS (APCI+) m/z: 375 (M+H)⁺.

EXAMPLE 3667-Chloro-6-(5-cyclohexylpyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To a mixture of6-(5-bromopyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(146 mg, 0.30 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (12 mg, 0.015 mmol) under dry nitrogen add withstirring a solution of 0.5 M cyclohexylzinc bromide in THF (3.0 mL, 1.5mmol). Degas, purge with dry nitrogen, and stir overnight at 60° C. Coolto ambient temperature, dilute with EtOAc, wash with water, dry overanhydrous MgSO₄ and concentrate in vacuo. Purify by chromatography onsilica gel eluting with hexane/EtOAc (5:1) to give3-tert-butoxycarbonyl-7-chloro-6-(5-cyclohexyl-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (46 mg, 32%). MS (APCI+) m/z: 487 (M+H)⁺. Use a method similarto the General Procedure 14 to give the title compound as a white solid.MS (APCI+) m/z: 387 (M+H)⁺.

EXAMPLE 3677-Chloro-6-(5-cyclopentylpyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the Example 366 to react6-(5-bromo-pyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith a solution of cyclopentylzinc bromide in THF. Use a method similarto the General Procedure 1-4, basic workup, and a method similar to theGeneral Procedure 2-1 to give the title compound as a tan solid. MS(APCI+) m/z: 373 (M+H)⁺.

EXAMPLE 3687-Chloro-6-(5-cyclohexylmethylpyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 366 to react6-(5-bromo-pyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith cyclohexylmethylzinc bromide. Use a method similar to the GeneralProcedure 1-5, basic workup, and a method similar to the GeneralProcedure 2-2 to give the title compound as a white solid. MS (APCI+)m/z: 401 (M+H)⁺.

EXAMPLE 3697-Chloro-6-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

In a sealed tube, add tris(dibenzylideneacetone)dipalladium(0) (3.44 mg,0.00376 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.98 mg,0.00752 mmol) to a mixture of6-(5-bromopyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(242 mg, 0.501 mmol), sodium tert-butoxide (96 mg, 1.0 mmol), 18-crown-6(13 mg, 0.050 mmol) and piperidine (496 μL, 5.01 mmol) in toluene (3mL). Flush the mixture with nitrogen and heat overnight. Cool to ambienttemperature, dilute with water and extract three times with EtOAc. Dryover anhydrous Na₂SO₄ and concentrate in vacuo. Purify by chromatographyon silica gel eluting with hexane/EtOAc (9:1) to give3-tert-butoxycarbonyl-7-chloro-6-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (179 mg, 73%).

Use a method similar to the General Procedure 1-5, using3-tert-butoxycarbonyl-7-chloro-6-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give, after basic workup and a method similar to the GeneralProcedure 2-2, the title compound as a yellow solid. MS (ES+) m/z: 388(M+H)⁺.

EXAMPLE 3707-Chloro-6-(5-pyrrolidin-1-yl-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 369, using6-(5-bromopyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand pyrrolidine to give the title compound as a pale yellow solid. MS(ES+) m/z: 374 (M+H)⁺.

EXAMPLE 3716-(5-Azepan-1-yl-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 369, using6-(5-bromopyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1Hbenzo[d]azepine and homopiperidine to give the title compound as ayellow solid. MS (ES+) m/z 402 (M+H)⁺.

EXAMPLE 3727-Chloro-6-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 369, using3-tert-butoxycarbonyl-7-chloro-6-(6-chloropyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand piperidine, to give the title compound as a white solid. MS (ES+)m/z: 388 (M+H)⁺.

EXAMPLE 3737-Chloro-6-[5-(4-fluorophenylethynyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Dissolve3-tert-butoxycarbonyl-6-(5-bromopyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.0 g, 2.07 mmol), tetrakistriphenylphosphine palladium(0) (120 mg,0.104 mmol), cuprous iodide-(20 mg, 0.105 mmol), triethylamine (2.60 mL)and 1-ethynyl-4-fluorobenzene (500 mg, 4.16 mmol) in DMF (8 mL). Degasthe mixture, purge with nitrogen, and heat at 65° C. for 3 days. Dilutethe mixture with water, extract three times with EtOAc, dry overanhydrous Na₂SO₄, and concentrate in vacuo. Purify by chromatography onsilica gel eluting with hexane/EtOAc (50:1) to give3-tert-butoxycarbonyl-7-chloro-6-[5-(4-fluorophenylethynyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a tan foam (1.02 g, 95%). MS (APCI+) m/z: 523 (M+H)⁺, 423 (M+H-Boc)⁺.Use a method similar to the General Procedure 14 to give the titlecompound as a tan powder. MS (APCI+) m/z: 423 (M+H)⁺.

EXAMPLE 374(Z)-7-Chloro-6-{5-[2-(4-fluorophenyl)vinyl]-pyridin-2-ylmethylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Dissolve3-tert-butoxycarbonyl-7-chloro-6-[5-(4-fluorophenylethynyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.0 g, 1.9 mmol), Lindlar catalyst (240 mg), and quinoline (0.8 mL) inmethanol (30 mL). Degas, purge with nitrogen, and stir under a balloonof hydrogen for 36 h. Filter the mixture and wash the catalyst withadditional methanol. Concentrate the filtrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (8:1) to give(Z)-3-tert-butoxycarbonyl-7-chloro-6-{5-[2-(4-fluoro-phenyl)-vinyl]-pyridin-2-ylmethylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a clear oil (630 mg, 63%). MS (APCI+) m/z: 525 (M+H), 425 (M+H-Boc)⁺.Use a method similar to the General Procedure 1-4 to give the titlecompound as a pale yellow solid. MS (APCI+) m/z: 425 (M+H)⁺.

EXAMPLE 3757-Chloro-6-[5-(2-fluoro-4-trifluoromethylbenzylcarbamoyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[c]azepineSuccinate

Dissolve3-tert-butoxycarbonyl-6-(5-carboxypyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(300 mg, 0.67 mmol) in DMF (5.0 mL). Treat successively with HATU (305mg, 0.802 mmol), N,N-diisopropylethylamine (140 μL, 0.804 mmol) and2-fluoro-4-(trifluoromethyl)benzylamine (260 mg, 1.34 mmol). Stirovernight at 40° C. Dilute the mixture with water, extract three timeswith EtOAc, dry over anhydrous Na₂SO₄, and concentrate in vacuo. Purifyby chromatography on silica gel eluting with hexane/EtOAc (3:1) to give3-tert-butoxycarbonyl-7-chloro-6-[5-(2-fluoro-4-trifluoromethyl-benzylcarbamoyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a foam (409 g, 98%). Use a method similar to the General Procedure1-4 to give, after basic work-up and a method similar to the GeneralProcedure 2-1, the title compound as an off-white solid. MS (APCI+) m/z:524 (M+H)⁺.

EXAMPLE 3767-Chloro-6-[5-(2,2-dimethylpropylcarbamoyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the Example 375, using3-tert-butoxycarbonyl-6-(5-carboxy-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand neopentylamine, to give the title compound as an off-white solid. MS(APCI+) m/z: 418 (M+H)⁺.

EXAMPLE 3777-Chloro-6-[5-(4-fluoro-benzylcarbamoyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the Example 375, using3-tert-butoxycarbonyl-6-(5-carboxy-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4-fluorobenzylamine, to give the title compound as an off-whitesolid. MS (APCI+) m/z: 456 (M+H)⁺.

EXAMPLE 3787-Chloro-6-[5-(cyclohexylmethylcarbamoyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 375, using3-tert-butoxycarbonyl-6-(5-carboxy-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand aminomethylcyclohexane to give, after deprotection by the GeneralProcedure 1-4, the title compound as a white solid. MS (APCI+) m/z: 444(M+H)⁺.

EXAMPLE 3796-(5-tert-Butylcarbamoyl-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 375, using3-tert-butoxycarbonyl-6-(5-carboxy-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand tert-butylamine to give, after deprotection by the General Procedure14, the title compound as an off-white solid. MS (APCI+) m/z: 404(M+H)⁺.

EXAMPLE 3807-Chloro-6-(4-trifluoromethoxybenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To a 4:1 mixture of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(102 mg, 0.27 mmol) in methanol (1.7 mL) under nitrogen, add potassiumhydroxide (0.9 g, 16.1 mmol) at ambient temperature. When the mixturebecomes homogenous, heat at 55-60° C. for 2-3 h, until TLC shows thedisappearance of starting material. Cool to ambient temperature, addaqueous saturated ammonium chloride solution, extract three times withdiethyl ether, dry over anhydrous MgSO₄, and concentrate in vacuo.Dissolve the crude3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepinein anhydrous DCM (2 mL) under nitrogen. Add with stirring DBU (80 μL,0.532 mmol) and 4-(trifluoromethoxy)benzyl bromide (77 μL, 0.53 mmol) atambient temperature and allow the reaction to continue overnight. Dilutewith aqueous saturated ammonium chloride solution, extract three timeswith diethyl ether, dry over anhydrous MgSO₄, and concentrate in vacuo.Treat a solution of the crude3-tert-butoxycarbonyl-7-chloro-6-(4-trifluoromethoxy-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepinein DCM (2 mL) with 2M hydrogen chloride in ether (excess) and continuestirring until TLC shows consumption of starting material. Concentratein vacuo and triturate the obtained solid with ether/pentane (10:90).Purify by preparative TLC eluting with 19:1 DCM/saturated ammonia inmethanol and convert to the hydrochloride by following a method similarto the General Procedure 2-2 to give the title compound as a white solid(48 mg, 43%). MS (APCI+) m/z: 388 (M+H)⁺.

Examples 381-383 may be prepared essentially as described in Example 380by using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriately substituted benzyl bromide. Example 382 may bepurified after deprotection by preparative reverse phase HPLC [Column:YMC ODS-AQ 335-120 Å 20×250 mm [S10-20 μm], eluent: gradient from 95:5to 5:95 A/B, flow rate: 15 mL/min; solvent A: water, 0.1% TFA, 1%isopropanol; solvent B: acetonitrile, 0.05% TFA, 1% isopropanol]. MS(ES+) data are included in the Table below.

MS (ES+) Ex. R Compound m/z 381 2-Cl 7-Chloro-6-(2-chloro-benzylthio)-338 2,3,4,5-tetrahydro-1H- (M + H)⁺ benzo[d]azepine Hydrochloride 3822-CN 7-Chloro-6-(2-cyano-benzylthio)- 329 2,3,4,5-tetrahydro-1H- (M +H)⁺ benzo[d]azepine Hydrochloride 383 4-Ph7-Chloro-6-(4-phenyl-benzylthio)- 380 2,3,4,5-tetrahydro-1H- (M + H)⁺benzo[d]azepine Hydrochloride

EXAMPLE 3847-Chloro-6-(4-fluoro-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

Use a method similar to the Example 380 to react3-tert-butoxylcarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]-azepinewith 4 fluorobenzyl bromide. Purify by preparative reverse phase HPLC[Column: YMC ODS-AQ 120 Å 20×250 mm [S10-20 μm], eluent: gradient from95:5 to 5:95 A/B, flow rate: 15 mL/min; solvent A: water, 0.1% TFA, 1%isopropanol; solvent B: acetonitrile, 0.05% TFA, 1% isopropanol] to givethe title compound as a white solid. MS (ES+) m/z: 322 (M+H)⁺.

Examples 385-386 may be prepared essentially as described in Example 384by using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriately substituted benzyl bromide. MS (ES+) data areincluded in the Table below.

MS Ex. R Compound (ES+) m/z 385 4-Cl 7-Chloro-6-(4-chloro-benzylthio)-338 2,3,4,5-tetrahydro-1H- (M + H)⁺ benzo[d]azepine Trifluoroacetate 3864-CN 7-Chloro-6-(4-cyano-benzylthio)- 329 2,3,4,5-tetrahydro-1H- (M +H)⁺ benzo[d]azepine Trifluoroacetate

EXAMPLE 3877-Chloro-6-(3,4-dichlorobenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

To a 4:1 mixture of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.521 mmol) in methanol (3.3 mL) under nitrogen add potassiumhydroxide (0.9 g, 16.07 mmol) at ambient temperature. When the mixturebecomes homogenous, heat at 55-60° C. for 2-3 h, until TLC shows thedisappearance of starting material. Cool to ambient temperature, addaqueous saturated ammonium chloride solution, extract three times withdiethyl ether, dry over anhydrous MgSO₄, and concentrate in vacuo.Dissolve the crude3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepinein anhydrous DCM (5 mL) under nitrogen. Add PS-DIEA (Argonaut, 3.83mmol/g, 410 mg, 1.57 mmol) and 3,4-dichlorobenzyl bromide (100 μL, 0.586mmol) at ambient temperature and allow the reaction to continueovernight. Filter the reaction mixture from the resin and rinse with DCM(2 mL), methanol (2 mL), DCM (2 mL), and methanol (2 mL). Concentrate invacuo. Treat a solution of the crude3-tert-butoxycarbonyl-7-chloro-6-(3,4-dichloro-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepinein DCM (2 mL) with a 2M hydrogen chloride in ether (excess) and continuestirring until TLC shows consumption of starting material. Concentratein vacuo and triturate the obtained solid with ether:pentane (10:90).Purify by preparative reverse phase HPLC (Column: Xterra Prep RP1819×250 mm; Solvent A: 10 mM aqueous ammonium carbonate, Solvent B:acetonitrile; 30-100% B over 20 minutes; flow rate 25 mL/min) to givethe title compound as a white solid (97 mg, 38%). MS (APCI+) m/z: 374(M+H)⁺.

Examples 388-393 may be prepared essentially as described in Example 387by using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriately substituted benzyl bromide. MS (ES+) data areincluded in the Table below.

MS (ES+ Ex. R Compound or APCI+) 388 3-Cl7-Chloro-6-(3-chloro-benzylthio)- 3382,3,4,5-tetrahydro-1H-benzo[d]azepine (M + H)⁺ Trifluoroacetate 389 3-F7-Chloro-6-(3-fluoro-benzylthio)- 3222,3,4,5-tetrahydro-1H-benzo[d]azepine (M + H)⁺ Trifluoroacetate 3903,4-diF 7-Chloro-6-(3,4-difluoro-benzylthio)- 3402,3,4,5-tetrahydro-1H-benzo[d]azepine (M + H)⁺ Trifluoroacetate 3913,5-diF 7-Chloro-6-(3,5-difluoro-benzylthio)- 3402,3,4,5-tetrahydro-1H-benzo[d]azepine (M + H)⁺ Trifluoroacetate 3923,4,5-triF 7-Chloro-6-(3,4,5-trifluoro- 358benzylthio)-2,3,4,5-tetrahydro-1H- (M + H)⁺ benzo[d]azepineTrifluoroacetate 393 3-OCF₃ 7-Chloro-6-(3- 388trifluoromethoxybenzylthio)-2,3,4,5- (M + H)⁺tetrahydro-1H-benzo[d]azepine Trifluoroacetate

EXAMPLE 3947,9-Dichloro-6-(3-fluorobenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

Obtain as minor product from the reaction of the 4:1 mixture of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo[d]azepinewith 3-fluorobenzyl bromide, using a method similar to the Example 387.Deprotect and isolate the title compound as a white solid afterpreparative reverse phase HPLC. MS (ES+) m/z: 356 (M+H)⁺.

EXAMPLE 3957,9-Dichloro-6-(3,4,5-trifluorobenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

Obtain as minor product from the reaction of the 4:1 mixture of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo[d]azepinewith 3,4,5-trifluorobenzyl bromide, using a method similar to theExample 387. Deprotect and isolate the title compound as a white solidafter preparative reverse phase HPLC. MS (APCI+) m/z: 392 (+H)⁺.

EXAMPLE 3967-Chloro-6-(2-nitro-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 387, using3-tert-butoxylcarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]-azepineand 2-nitrobenzyl bromide to give, after chromatography eluting withhexane/EtOAc (10:1) and deprotection by the General Procedure 1-4, thetitle compound as an off-white powder. MS (APCI+) m/z: 349 (M+H)⁺.

Examples 397-399 may be prepared essentially as described in Example 396by using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriately substituted benzyl bromide. MS (ES+) data areincluded in the Table below.

MS (ES+ or Ex. R Compound APCI+) 397 2-OCF₃ 7-Chloro-6-(2- 388trifluoromethoxybenzylthio)-2,3,4,5- (M + H)⁺tetrahydro-1H-benzo[d]azepine Hydrochloride 398 3-OPh7-Chloro-6-(3-phenoxybenzylthio)- 396 2,3,4,5-tetrahydro-1H- (M + H)⁺benzo[d]azepine Hydrochloride 399 3,5-diCF₃ 7-Chloro-6-(3,5- 440bistrifluoromethylbenzylthio)-2,3,4,5- (M + H)⁺tetrahydro-1H-benzo[d]azepine Hydrochloride

EXAMPLE 4007,9-Dichloro-6-(3,5-bis-trifluoromethylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride (2148393)

Obtain as minor product from the reaction of the 4:1 mixture of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo[d]azepinewith 3,5-bis-trifluoromethylbenzyl bromide, using a method similar tothe Example 396. Deprotect the crude mixture and purify by preparativereverse phase HPLC (Column: Xterra Prep RP18 19×250 mm; solvent A: 10 mMaqueous ammonium carbonate; solvent B: acetonitrile; 30-100% B over 20minutes; flow rate 25 mL/min). Use a method similar to the GeneralProcedure 2-2 to give the title compound as a white solid. MS (APCI+)m/z: 474 (M+H)⁺.

EXAMPLE 4017-Chloro-6-(2,6-difluorobenzylthio-)2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 330, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2,6-difluorobenzyl bromide to give, after deprotection by theGeneral Procedure 1-4, the title compound.

EXAMPLE 4027-Chloro-6-(2-trifluoromethylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 347 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith 2-trifluoromethylbenzyl bromide. Use a method similar to theGeneral Procedure 1-4 to give the title compound as a waxy tan solid. MS(APCI+) m/z: 372 (M+H)⁺.

EXAMPLE 4037-Chloro-6-(4-methoxycarbonylbenzylthio)-2,3,4,5-tetrahydro-benzo[d]azepineHydrochloride

Use a method similar to the Preparation 177, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand methyl 4-(bromomethyl)benzoate to give, after deprotection by theGeneral Procedure 14, the title compound as a white solid. MS (ES+) m/z:362 (M+H)⁺.

EXAMPLE 4047-Chloro-6-(3-methoxycarbonylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 347 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith methyl 3-(bromomethyl)benzoate. Use a method similar to the GeneralProcedure 1-5, basic workup, and a method similar to the GeneralProcedure 2-2 to give the title compound. MS (APCI+) m/z: 362 (M+H)⁺.

EXAMPLE 4057-Chloro-6-(2-methoxycarbonylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 347, using the 4:1 mixture of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo[d]azepinewith methyl 2-(bromomethyl)benzoate. Use a method similar to the GeneralProcedure 1-4 and purify by preparative reverse phase HPLC (Column:Xterra Prep RP18 19×250 mm; solvent A: 10 mM aqueous ammonium carbonate,solvent B: acetonitrile; 30-100% B over 20 minutes; flow rate 25mL/min). Use a method similar to the General Procedure 2-2, to give thetitle compound as a white solid. MS (ES+) m/z: 362 (M+H)⁺.

EXAMPLE 4067,9-Dichloro-6-(2-methoxycarbonylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Obtain the free base of the title compound as a minor product fromExample 405, after preparative reverse phase HPLC (Column: Xterra PrepRP18 19×250 mm; solvent A: 10 mM aqueous ammonium carbonate; solvent B:acetonitrile; 30-100% B over 20 minutes; flow rate 25 mL/min). Use amethod similar to the General Procedure 2-2 to give the title compoundas a white solid MS (ES+) m/z: 396 (M+H)⁺.

EXAMPLE 4076-(4-Benzoylbenzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 380 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith 4-(bromomethyl)benzophenone. Purify by preparative reverse phaseHPLC (Column: Xterra Prep RP18 19×250 mm; Solvent A: 10 mM aqueousammonium carbonate, Solvent B: acetonitrile; 30-100% B over 20 minutes;flow rate 25 mL/ruin). Use a method similar to the General Procedure 2-2to give the title compound as a white solid. MS (ES+) m/z: 408 (M+H)⁺.

EXAMPLE 4087-Chloro-6-[4-(3,3-dimethyl-2-oxo-butoxy)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 7, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(577 mg, 1.5 mmol) and 1-(4-bromomethylphenoxy)-3,3-dimethylbutan-2-one(556 mg, 1.95 mmol) to give, after chromatography on silica gel elutingwith EtOAc/hexane (1:5),3-tert-butoxycarbonyl-7-chloro-6-[4-(3,3-dimethyl-2-oxo-butoxy)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil (669 mg, 86%). MS (ES+) m/z: 518 (M+H)⁺.

Use a method similar to the General Procedure 1-5 to deprotect3-tert-butoxycarbonyl-7-chloro-6-[4-(3,3-dimethyl-2-oxo-butoxy)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(669 mg, 1.29 mmol). Purify by chromatography on silica gel eluting withDCM/2M ammonia in methanol (92:8) to give the free base of the titlecompound as a colorless oil (349 mg, 64%). MS (ES+) m/z: 418 (M+H)⁺. Usea method similar to the General Procedure 2-1 to give the titlecompound.

EXAMPLE 4097-Chloro-6-[3-chloro-4-(3,3-dimethyl-2-oxo-butoxy)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the Example 408, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 1-(4-bromomethyl-3-chlorophenoxy)-3,3-dimethylbutan-2-one to givethe title compound. MS (ES+) m/z: 452 (M+H)⁺.

EXAMPLE 4107-Chloro-6-(4-methanesulfonylmethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 1-4, using3-tert-butoxycarbonyl-7-chloro-6-(4-methanesulfonylmethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give the title compound as a white solid. MS (ES+) m/z: 396 (M+H)⁺.

EXAMPLE 4117-Chloro-6-(5-chloro-thiophen-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 387, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2-chloro-5-(chloromethyl)thiophene to give, after hydrochlorideformation by the General Procedure 2-2, the title compound as a brownsolid. MS (APCI+) m/z: 344 (M+H)⁺.

EXAMPLE 4127-Chloro-6-(pyridin-4-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 387, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4-bromomethylpyridine hydrobromide to give, after hydrochlorideformation by the General Procedure 2-2, the title compound as a whitesolid. MS (APCI+) m/z: 305 (M+H)⁺.

EXAMPLE 4137-Chloro-6-(6-methyl-pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 387, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2-chloromethyl-6-methylpyridine to give, after chromatography onsilica gel eluting with hexane/EtOAc (4:1) and deprotection by theGeneral Procedure 1-4, the title compound as a white solid. MS (ES+)m/z: 319 (M+H)⁺.

EXAMPLE 4147-Chloro-6-[3-fluoro-4-(3-methylbutyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To6-(4-bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.210 mg, 0.42 mmol) anddichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)dichloromethane adduct (17 mg, 0.021 mmol) add 0.5 M 3-methylbutylzincbromide in THF (4.2 mL, 2.10 mmol). Degas, purge with dry nitrogen, andstir overnight at 80° C. Cool to ambient temperature, dilute with EtOAc,wash with water, dry over anhydrous MgSO₄ and concentrate in vacuo.Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1)to give3-tert-butoxycarbonyl-7-chloro-6-[3-fluoro-4-(3-methylbutyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (85 mg, 42%). Use a method similar to the GeneralProcedure 1-4 to give the title compound as a white solid. MS (ES+) m/z:392 (M+H)⁺.

EXAMPLE 4157-Chloro-6-(4-cyclohexylmethyl-3-fluorobenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the Example 414 to react6-(4-bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith (cyclohexyl)methylzinc bromide. Use a method similar to the GeneralProcedure 1-4, basic work-up, and a method similar to the GeneralProcedure 2-1, to give the title compound as a white solid. MS (ES+)m/z: 418 (M+H)⁺.

EXAMPLE 4167-Chloro-6-(4-cyclohexyl-3-fluorobenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 414, using6-(4-bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand cyclohexylzinc bromide. Use a method similar to the GeneralProcedure 1-4, basic work-up, and a method similar to the GeneralProcedure 2-1, to give the title compound as a white solid. MS (ES+)m/z: 404 (M+H)⁺.

EXAMPLE 4177-Chloro-6-(2,5′-difluoro-2′-methoxybiphenyl-4-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Degas a stirred mixture of6-(4-bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(212 mg, 0.424 mmol), 5-fluoro-2-methoxybenzene boronic acid (108 mg,0.636 mmol), potassium carbonate (292 mg, 2.12 mmol), triphenylphosphine(11 mg, 0.0424 mmol) and bis(triphenylphosphine)-palladium(II) chloride(15 mg, 0.0212 mmol) in dioxane (3 mL) and water (1 mL). Purge with drynitrogen and heat at 100° C. for 5 h. Cool to ambient temperature, addwater, extract three times with EtOAc, dry over anhydrous Na₂SO₄ andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (9:1) to give3-tert-butoxycarbonyl-7-chloro-6-(2,5′-difluoro-2′-methoxy-biphenyl-4-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas yellow oil (216 mg, 93%). Use a method similar to the GeneralProcedure 1-4 to give the title compound as a yellow foam. MS (ES+) m/z:446 (M+H)⁺.

EXAMPLE 4187-Chloro-6-(2′-chloro-2-fluorobiphenyl-4-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 417, using 2-chlorophenylboronicacid to give, after deprotection by the General Procedure 1-4, the titlecompound as a white solid. MS (ES+) m/z: 432 (M+H)⁺.

EXAMPLE 4197-Chloro-6-(3-fluoro-4-piperidin-1-yl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

In a sealed tube, add tris(dibenzylideneacetone)dipalladium (13 mg,0.014 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19 mg,0.029 mmol) to a mixture of6-(4-bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(957 mg, 1.91 mmol), sodium tert-butoxide (367 mg, 3.83 mmol),18-crown-6 (50 mg, 0.191 mmol) and piperidine (944 μl, 9.57 mmol) intoluene (10 mL). Flush the mixture with nitrogen and heat overnight.Cool to ambient temperature, dilute with water and extract three timeswith EtOAc. Dry over anhydrous Na₂SO₄ and concentrate in vacuo. Purifyby chromatography on silica gel eluting with hexane/EtOAc (9:1) to give3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-piperidin-1-yl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (511 mg, 33%). Use a method similar to the GeneralProcedure 1-4 to give the title compound as a white solid. MS (ES+) m/z:405 (M+H)⁺.

EXAMPLE 4207-Chloro-6-(3-fluoro-4-pyrrolidin-1-yl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 419 to react6-(4-bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith pyrrolidine. Use a method similar to the General Procedure 1-4 togive the title compound as a white solid. MS (ES+) m/z: 391 (M+H)⁺.

EXAMPLE 4216-(4-Azepan-1-yl-3-fluorobenzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 419 to react6-(4-bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith homopiperidine. Use a method similar to the General Procedure 14 togive the title compound as a white solid. MS (ES+) m/z: 419 (M+H)⁺.

EXAMPLE 4227-Chloro-6-(4-chloro-3-pyrrolidin-1-yl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepinehydrochloride

Use a method similar to the Example 419, using6-(3-bromo-4-chloro-benzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand pyrrolidine to give, after deprotection using a method similar tothe General Procedure 1-4, the title compound as a white solid. MS (ES+)m/z: 407 (M+H)⁺.

EXAMPLE 4237-Chloro-6-(4-cyclohexylmethoxybenzylthio)-3-tert-butoxycarbonyl--2,3,4,5-tetrahydro-1H-benzo[d]azepine Hydrochloride

Use a method similar to the Preparation 177, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4-(chloromethyl)phenyl acetate to give6-(4-acetoxybenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a white solid.

To6-(4-acetoxybenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(532 mg, 1.15 mmol) in methanol (8 mL) at ambient temperature add withstirring a solution of potassium carbonate (796 mg, 5.77 mmol) in water(4 mL) and stir the mixture for 2 h. Dilute with water, extract threetimes with EtOAc, dry over anhydrous Na₂SO₄, and concentrate in vacuo.To a portion of the crude phenol thus obtained (204 mg, 0.487 mmol) inTHF (5 mL), add with stirring diisopropyl azodicarboxylate (216 μl, 1.71mmol) followed by triphenylphosphine (306 mg, 1.17 mmol) andcyclohexylmethanol (619 mg, 5.42 mmol). Heat at 60° C. for 3 h, cool toambient temperature and concentrate in vacuo. Purify by chromatographyon silica gel eluting with hexane/EtOAc (9:1) to give3-tert-butoxycarbonyl-7-chloro-6-(4-cyclohexylmethoxy-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil (176 mg, 70%). Use a method similar to the GeneralProcedure 1-4 to give the title compound as a white solid. MS (ES+) m/z:416 (M+H)⁺.

EXAMPLE 4247-Chloro-6-(4-cycloheptyloxybenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 423 to react6-(4-acetoxybenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith cycloheptanol. Use a method similar to the General Procedure 1-4 togive the title compound as a white solid. MS (ES+) m/z: 416 (M+H)⁺.

EXAMPLE 4257-Chloro-6-[4-(2,2-dimethylpropoxy)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Preparation 177 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 1-bromomethyl-4-(2,2-dimethylpropoxy)-benzene. Use a method similarto the General Procedure 1-4 to give the title compound as a whitesolid. MS (ES+) m/z: 390 (M+H)⁺.

EXAMPLE 4267-Chloro-6-(2-methanesulfonylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Preparation 177, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 1-bromomethyl-2-methanesulfonyl-benzene to give, after deprotectionby the General Procedure 1-4, the title compound and as a white solid.MS (APCI+) m/z: 382 (M+H)⁺.

EXAMPLE 4277-Chloro-6-(4-methanesulfonylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 380, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4 methylsulfonylbenzyl bromide to give, after hydrochlorideformation by the General Procedure 2-2, the title compound as a whitesolid. MS (ES+) m/z: 382 (M+H)⁺.

EXAMPLE 4287-Chloro-6-[4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfinyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(723 mg, 1.88 mmol) in methanol (10 mL) add potassium hydroxide pellets(3.34 g, 60.2 mmol) and stir mixture at 50° C. for 2 h. Cool to ambienttemperature, add aqueous saturated ammonium chloride, extract threetimes with EtOAc, dry over anhydrous Na₂SO₄, and concentrate in vacuo togive the crude3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Dissolve the compound in DMF (5 mL), add cesium carbonate (920 mg, 2.82mmol) and1-bromomethyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethyl-propane-1-sulfinyl)-benzene(824 mg, 2.071 mmol) and stir 2 h at ambient temperature. Dilute withwater, extract three times with EtOAc, dry over anhydrous Na₂SO₄, andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (9:1) to give3-tert-butoxycarbonyl-7-chloro-6-[4-(3,3,3-trifluoro-2-methyl-2-trifluoromethyl-propane-1-sulfinyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (986 mg, 83%). Use a method similar to the GeneralProcedure 14 to give the title compound as a white foam. MS (ES+) m/z:530 (M+H)⁺.

Examples 429-432 may be prepared essentially as described in Example 428by using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith the appropriately substituted benzyl bromide. MS (ES+) data areincluded in the Table below.

MS (ES+ or Ex. SO₂R Compound APCI+) 429

7-Chloro-6-[4-(2,2-dimethyl-propane-1-su1fonyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]aze-pineHydrochloride 438(M + H)⁺ 430

7-Chloro-6-[4-(3,3,3-trifluoro-2-methyl-2-trifiuoromethyl-propane-1-sulfonyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]aze-pineHydrochloride 546(M + H)⁺ 431

7-Chloro-6-[4-(4-trifluoromethyl-benzenesulfonyl)-benzylthio]-1,2,4,5-tetrahydro-benzo[d]aze-pineHydrochloride 512(M + H)⁺ 432

7-Chloro-6-(4-cyclohexyl-methanesulfonyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]aze-pineHydrochloride 464(M + H)⁺

EXAMPLE 4337-Chloro-6-[4-(2,4-difluoro-phenylmethanesulfonyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the Example 428 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith 1-(4-bromomethyl-benzenesulfonylmethyl)-2,4-difluoro-benzene. Use amethod similar to the General Procedure 1-4, basic work-up, and a methodsimilar to the General Procedure 2-1, to give the title compound as awhite solid. MS (ES+) m/z: 494 (M+H)⁺.

EXAMPLE 4347-Chloro-6-[4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the Example 428 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith1-bromomethyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethyl-propylthio)benzene.Use a method similar to the General Procedure 1-5, basic workup, and amethod similar to the General Procedure 2-1, to give the title compoundas a white solid. MS (APCI+) m/z: 514 (M+H)⁺.

EXAMPLE 4357-Chloro-6-[4-(3,3-dimethylbutyryl)-benzylthio]-1,2,4,5-tetrahydro-benzo[d]azepineHydrochloride

Use a method similar to the Example 428 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith 1-(4-bromomethylphenyl)-3,3-dimethylbutan-1-one. Use a methodsimilar to the General Procedure 1-4, basic workup, and a method similarto the General Procedure 2-2 to give the title compound as a whitesolid. MS (APCI+) m/z: 402 (M+H)⁺.

EXAMPLE 436(±)-7-Chloro-6-[1-(2-cyanophenyl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Preparation 177, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand (±)-2-(1-bromoethyl)benzonitrile to give, after deprotection by theGeneral Procedure 1-4, the title compound as a white solid. MS (APCI+)m/z: 343 (M+H)⁺.

EXAMPLE 437(−)-7-Chloro-6-[1-(2-cyanophenyl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Dissolve(±)-7-chloro-6-[1-(2-cyanophenyl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate (326 mg, 1.0 mmol) in DCM (5 mL) and pyridine (0.4 mL, 5mmol). Add di-tert-butyl-dicarbonate (270 mg, 1.2 mmol) and stir themixture for 16 h at ambient temperature. Wash the mixture with 5Naqueous NaOH and saturated aqueous NaHCO₃ successively. Collect theorganic layer and concentrate in vacuo. Purify the residue bychromatography on silica gel eluting with hexane/EtOAc (1:1) to obtain(±)-3-tert-butoxycarbonyl-7-chloro-6-[1-(2-cyanophenyl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(393 mg, 93%). Separate the enantiomers of (±)3-tert-butoxycarbonyl-7-chloro-6-[1-(2-cyanophenyl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineby chiral normal phase chromatography (Chiralpak AD 8×30 cm column,eluting with heptane/isopropylamine, 95:5).

Take the second eluting isomer and deprotect using the General Procedure1-5. Purify with SCX chromatography. Use a method similar to the GeneralProcedure 2-2 to obtain the title compound (125 mg, 37%). MS (ES+) m/z:343 (M+H)⁺. [α]²⁰ _(D) −112° (c 0.5, CH₃OH).

EXAMPLES 438 AND 4396-[4-(2-Butyl-2H-pyrazol-3-yl)-benzylthio]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride and6-[4-(1-Butyl-1H-pyrazol-3-yl)-benzylthio]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

4-Acetylbenzyl bromide: Use a method similar to the Preparation 184,using 4-methylacetophenone, to give the desired intermediate as a whitesolid.6-(4-Acetylbenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Use a method similar to the Example 380, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4-acetylbenzyl bromide to give, after chromatography eluting withhexane/EtOAc (15:1), the desired intermediate as a white solid. MS(APCI+) m/z 346 (M+H-Boc)⁺.3-tert-Butoxycarbonyl-7-chloro-6-[4-(3-dimethylaminoacryloyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Heat a solution of6-(4-acetylbenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.0 g, 2.2 mmol) in toluene (10 mL) at 110° C. overnight in thepresence of tert-butoxy-bis(dimethylamino)-methane (1.0 mL, 4.84 mmol).Concentrate in vacuo to provide the desired intermediate as a dark oil(1.2 g, 100%). MS (APCI+) m/z 401 (M+H-Boc)⁺.6-[4-(1-Butyl-1H-pyrazol-3-yl)-benzylthio]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride: To a stirred mixture of3-tert-butoxycarbonyl-7-chloro-6-[4-(3-dimethylaminoacryloyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(240 mg, 0.475 mmol), butylhydrazine oxalate (102 mg, 0.574 mmol),sodium carbonate (55 mg, 0.444 mmol) in water (8 mL) and methanol (10mL) add acetic acid (ca. 3-6 drops) to pH 5. Heat overnight at 70° C.Concentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (10:1) to give a mixture of the desired intermediates,3-tert-butoxycarbonyl-6-[4-(2-butyl-2H-pyrazol-3-yl)-benzylthio]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(65 mg, 32%), MS (APCI+) m/z: 426 (M+H-Boc)⁺ and3-tert-butoxycarbonyl-6-[4-(1-butyl-1H-pyrazol-3-yl)-benzylthio]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(100 mg, 50%), MS (APCI+) m/z: 426 (M+H-Boc)⁺.

Use a method similar to the General Procedure 1-4, using3-tert-butoxycarbonyl-6-[4-(2-butyl-2H-pyrazol-3-yl)-benzylthio]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine,to give6-[4-(2-butyl-2H-pyrazol-3-yl)-benzylthio]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(Example 438) as a white solid. MS (APCI+) m/z: 426 (M+H)⁺.

Use a method similar to the General Procedure 1-4, using3-tert-butoxycarbonyl-6-[4-(1-butyl-1H-pyrazol-3-yl)-benzylthio]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine,to give6-[4-(1-butyl-1H-pyrazol-3-yl)-benzylthio]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(Example 439) as a white solid. MS (APCI+) m/z: 426 (M+H)⁺.

EXAMPLE 440 6-(4tert-Butylcarbamoyl-3-fluorobenzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

3-tert-Butoxycarbonyl-7-chloro-6-(3-fluoro-4-methoxycarbonylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Use a method similar to the Example 428, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand methyl 4-bromomethyl-2-fluorobenzoate, to give the desiredintermediate as a white solid.3-tert-Butoxycarbonyl-6-(4-carboxy-3-fluorobenzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Heat a stirred solution of3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-methoxycarbonylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(3.56 g, 7.44 mmol) in THF (50 mL) and water (40 mL) overnight at 65° C.in the presence of potassium hydroxide (8.30 g, 148.77 mmol). Cool themixture to 0° C., add slowly a 1N solution of hydrochloric acid until pH5. Extract three times with EtOAc, dry over anhydrous Na₂SO₄ andconcentrate in vacuo to provide the desired intermediate as a whitesolid (3.5 g, 99%).6-(4-tert-Butylcarbamoyl-3-fluorobenzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride: To a solution of3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.1 g, 2.36 mmol) in DMF (7 mL), add tert-butylamine (12.05 g, 165.2mmol), EDC (1.81 g, 9.44 mmol) and HOBt (1.44 g, 10.62 mmol) and stir ina sealed tube at 70° C. overnight. Dilute with EtOAc, wash with water,dry over anhydrous MgSO₄ and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (9:1) to give3-tert-butoxycarbonyl-6-(4-tert-butylcarbamoyl-3-fluorobenzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a clear oil. MS (APCI+) m/z: 421 (M+H)⁺. Use a method similar to theGeneral Procedure 1-4 to give the title compound as a white powder. MS(APCI+) m/z: 421 (M+H)⁺.

Examples 441-447 may be prepared essentially as described in Example 440by reacting3-tert-butoxycarbonyl-6-(4-carboxy-3-fluorobenzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith the appropriate amine. MS (ES+) data are included in the Tablebelow.

MS (ES+ Ex. N—R R′ Compound or APCI+) 441 N-(n-Pr) H7-Chloro-6-(3-fluoro-4-n- 407 propylcarbamoyl-benzylthio)- (M + H)⁺2,3,4,5-tetrahydro-1H- benzo[d]azepine Hydrochloride 442 N-(i-Bu) H6-(4-iso-Butylcarbamoyl-3-fluoro- 421 benzylthio)-7-chloro-2,3,4,5- (M +H)⁺ tetrahydro-1H-benzo[d]azepine Hydrochloride 443 N-(n-Pr) n-Pr7-Chloro-6-(4-dipropylcarbamoyl- 449 3-fluoro-benzylthio)-2,3,4,5- (M +H)⁺ tetrahydro-1H-benzo-[d]azepine Hydrochloride 444

H7-Chloro-6-[3-fluoro-4-(4-fluoro-benzylcarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 473(M + H)⁺ 445

H7-Chloro-6-(4-cyclohexylcarbamoyl-3-fluoro-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 447(M + H)⁺ 446

7-Chloro-6-[3-fluoro-4-(2-isobutyl-pyrrolidine-1-carbonyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 475(M + H)⁺ 447

7-Chloro-6-{3-fluoro-4-[3-(4-fluoro-phenyl)-pyrrolidine-1-carbonyl]-benzylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepine-Hydrochloride513(M + H)⁺

EXAMPLE 448(S)-(+)-6-(4-sec-Butylcarbamoyl-3-fluorobenzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

3-tert-Butoxycarbonyl-7-chloro-6-(4-chlorocarbonyl-3-fluorobenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:To a solution of3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.95 g, 4.21 mmol) in DCM (20 mL) at 0° C. under nitrogen, add threedrops of DMF and oxalyl chloride (1.06 g, 8.41 mmol). Stir for 2 h andconcentrate in vacuo to afford the desired intermediate as a yellow oil(1.93 g, 95%).(S)-3-tert-Butoxycarbonyl-6-(4-sec-butylcarbamoyl-3-fluorobenzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine:To a solution of3-tert-butoxycarbonyl-7-chloro-6-(4-chlorocarbonyl-3-fluoro-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(415 mg, 0.860 mmol) in DCM (10 mL), add (S)-(+)-sec-butylamine (1.0 g,13.7 mmol) and stir at ambient temperature for 30 min. Concentrate invacuo and purify by chromatography on silica gel eluting withhexane/EtOAc (4:1) to give the desired intermediate as a pale oil (352mg, 79%). MS (APCI+) m/z: 421 (M+H-Boc)⁺.

(S)-(+)-(4-sec-Butylcarbamoyl-3-fluorobenzylthio)-7-chloro-2,3,4-tetrahydro-1H-benzo[d]azepineHydrochloride: Use a method similar to the General Procedure 1-4, using(+)-3-tert-butoxycarbonyl-6-(4-sec-butylcarbamoyl-3-fluoro-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine,to give the title compound as a pale solid. MS (APCI+) m/z: 421 (M+H)⁺.[α]²⁰ _(D) +8.7° (c 0.5, CH₃OH).

Examples 449-454 may be prepared essentially as described in Example 448by reacting3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith the appropriate amine. Optical rotation and MS (ES+) data areincluded in the Table below.

[α]²⁰ _(D) MS Ex. NH—R Compound (c, solvent (ES+) m/z 449

(R)-(−)-6-(4-sec-Butylcarbamoyl-3-fluoro-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride −7.0° (c 0.5,CH₃OH). 421(M + H)⁺ 450

7-Chloro-6-[4-(2-chloro-benzylcarbamoyl)-3-fluoro-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride — 489(M + H)⁺ 451

7-Chloro-6-[3-fluoro-4-(2-trifluoromethyl-benzylcarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride — 523(M + H)⁺ 452

7-Chloro-6-[3-fluoro-4-(2-fluoro-4-trifluoromethyl-benzyl-carbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]aze-pineHydrochloride— 541(M + H)⁺ 453

(S)-(−)-7-Chloro-6-{3-fluoro-4-[1-(4-fluoro-phenyl)-ethyl-carbamoyl]-benzylthio}-2,3,4,5-tetrahydro-1H-benzo-[d]azepineHydrochloride−25.8° (c 0.5,CH₃OH) 487(M + H)⁺ 454

(R)-(+)-7-Chloro-6-{3-fluoro-4-[1-(4-fluoro-phenyl)-ethyl-carbamoyl]-benzylthio}-2,3,4,5-tetrahydro-1H-benzo-[d]azepineHydrochloride+24.9° (c 0.5,CH₃OH) 487(M + H)⁺

EXAMPLE 4557-Chloro-6-(3-fluoro-4-isobutylcarbamoyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the Example 448 to react3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith isobutylamine. Use a method similar to the General Procedure 14,basic work-up, and a method similar to the General Procedure 2-1 to givethe title compound as a white solid. MS (ES+) m/z: 403 (M+H)⁺.

EXAMPLE 4567-Chloro-6-(4-cyclohexylcarbamoylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the Preparation 177 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith 4-chloromethyl-N-cyclohexylbenzamide. Use a method similar to theGeneral Procedure 1-5, basic workup, and a method similar to the GeneralProcedure 2-1 to give the title compound as a white solid MS (ES+) m/z:429 (M+H)⁺.

Examples 457-465 may be prepared essentially as described in Example 456by using3-tert-butoxycarbonyl-7-chloro-6-diethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriately substituted benzyl chloride. Optical rotation andMS (ES+) data are included in the Table below.

MS [α]²⁰ _(D) (ES+ or Ex. NH—R Compound (c, solvent) (APCI+) 457

7-Chloro-6-[4-(2-fluoro-4-trifluoromethyl-benzylcarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate — 523(M + H)⁺ 458

[4-(3,5-Bis-trifluoromethyl-benzylcarbamoyl)-benzylthio]-7-chloro-2,3,4,5-tetrahydro-1H-1H-benzo[d]azepineSuccinate — 573(M + H)⁺ 459

7-Chloro-6-[4-(4-fluoro-2-trifluoromethyl-benzylcarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate — 523(M + H)⁺ 460

(S)-(+)-7-Chloro-6-[4-(1-cyclohexyl-ethylcarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate +11.2° (c 0.5,CH₃OH) 457(M + H)⁺ 461

(R)-(−)-7-Chloro-6-[4-(1-cyclohexyl-ethylcarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate +11.3° (c 0.5,CH₃OH). 457(M + H)⁺ 462

(R)-(+)-7-Chloro-6-{4-[1-(4-fluoro-phenyl)-ethylcarbamoyl]-benzylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate +2.2° (c 0.5,CH₃OH) 469(M + H)⁺ 463

(S)-(−)-7-Chloro-6-{4-[1-(4-fluoro-phenyl)-ethylcarbamoyl]-benzylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate +1.6° (c 0.5,CH₃OH) 469(M + H)⁺ 464

(R)-(−)-7-Chloro-6-{4-[1-(4-chloro-phenyl)-ethylcarbamoyl]-benzylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate −5.8° (c 0.5,CH₃OH) 485(M + H)⁺ 465

(S)-(+)-7-Chloro-6-{4-[1-(4-chloro-phenyl)-ethylcarbamoyl]-benzylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate +5.5° (c 0.5,CH₃OH) 485(M + H)⁺

EXAMPLE 4667-Chloro-6-[4-(2,2-dimethyl-propylcarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 456, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4-chloromethyl-N-(2,2-dimethyl-propyl)-benzamide to give, afterdeprotection by a method similar to the General Procedure 14, the titlecompound as a white solid. MS (ES+) m/z: 417 (M+H)⁺.

Examples 467-471 may be prepared essentially as described in Example 466by using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriately substituted benzyl chloride. MS (ES+) data areincluded in the Table below.

MS (ES+) Ex. NH—R Compound m/z 467

6-(4-tert-Butylcarbamoyl-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride403(M + H)⁺ 468

7-Chloro-6-[4-(cyclohexylmethyl-carbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride443(M + H)⁺ 469

7-Chloro-6-[4-(4-trifluoromethyl-benzylcarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 505(M + H)⁺ 470

7-Chloro-6-[4-(3,4-difluoro-benzylcarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 473(M + H)⁺ 471

7-Chloro-6-[4-(2,3,4-trifluoro-benzylcarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 491(M + H)⁺

EXAMPLE 472(±)-7-Chloro-6-(1-methoxycarbonyl-1-phenyl-methyllthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 1-4, using(±)-3-tert-butoxycarbonyl-7-chloro-6-(1-methoxycarbonyl-1-phenyl-methyllthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine,to give the title compound as a white solid. MS (ES+) m/z 362 (M+H)⁺.

EXAMPLE 473(±)-7-Chloro-6-(2-hydroxy-1-phenyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To a stirred solution of(±)-3-tert-butoxycarbonyl-6-(1-carboxy-1-phenyl-methyllthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(220 mg, 0.447 mmol) in THF (10 mL) at 0° C., add a solution of 1Mborane in THF (1.4 mL, 1.4 mmol). Continue stirring for 2 h at 0° C. andthen overnight at ambient temperature. Quench by slow addition ofmethanol, stir 1 h at ambient temperature and concentrate in vacuo. Addaqueous saturated ammonium chloride, extract three times with EtOAc, dryover anhydrous MgSO₄, and concentrate in vacuo. Purify by chromatographyon silica gel eluting with 19:1 DCM/saturated ammonia in methanol. Use amethod similar to the General Procedure 1-4 to give the title compoundas a white solid. MS (ES+) m/z: 334 (M+H)⁺.

EXAMPLE 4747,9-Dichloro-6-methoxycarbonylmethylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Obtain as minor product from the reaction of the 4:1 mixture of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo[d]azepinewith methyl bromoacetate, using a method similar to the Example 347. Usea method similar to the General Procedure 1-4 to give the title compoundas a white solid. MS (ES+) m/z: 320 (M+H)⁺.

EXAMPLE 4756-(4-Benzyloxybenzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Dissolve3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(706 mg, 1.84 mmol) in methanol (20 mL). Add potassium hydroxide (3.5 g,55 mmol) and heat the mixture at reflux for 3 h Cool to ambienttemperature. Pour reaction in saturated aqueous NH₄Cl solution. Extractthree times with EtOAc. Combine organic extracts, dry over Na₂SO₄ andconcentrate in vacuo to obtain crude3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine(602 mg, 100%). Dissolve3-tert-butoxycarbonyl-7-chloro-6mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine(282 mg, 0.9 mmol) in acetone (30 mL). Add 4-benzyloxybenzyl chloride(251 mg, 1.08 mmol), potassium carbonate (powder) (373 mg, 2.7 mmol) andpotassium iodide (powder) (15 mg, 0.1 mmol) and reflux for 16 h. Coolthe reaction to ambient temperature, dilute with acetone, filter andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (1:0 and 17:3) to give6-(4-benzyloxybenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(309 mg, 67%). MS (ES+) m/z: 510 (M+H)⁺.

Use a method similar to the General Procedure 1-4 and purify bychromatography on silica gel eluting with DCM/2M ammonia in methanol(95:5) to obtain the free base of the title compound (230 mg, 92%). MS(ES+) m/z: 410 (M+H)⁺. Use a method similar to the General Procedure 2-1to obtain the title compound.

EXAMPLE 4767-Chloro-6-[(2-fluoro-4-phenoxy)benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the Example 475, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 1-bromomethyl-2-fluoro-4-phenoxybenzene to provide, afterchromatography on silica gel eluting with hexane/EtOAc (85:15),3-tert-butoxycarbonyl-7-chloro-6-[(2-fluoro-4-phenoxy)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(384 mg, 83%). MS (ES+) m/z: 414 (N-Boc+2H)⁺.

Use a method similar to the General Procedure 1-4 and purify bychromatography on silica gel eluting with DCM/2M ammonia in methanol(95:5) to obtain the free base of the title compound (203 mg, 65%). MS(ES+) m/z: 414 (M+H)⁺. Use a method similar to the General Procedure 2-1to obtain the title compound.

EXAMPLE 4777-Chloro-6-[2-(4-fluorophenyl)-2-oxo-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 475, using crude3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2-bromo-4′-fluoroacetophenone (239 mg, 1.1 mmol) to provide, afterstirring at ambient temperature for 16 h and purification bychromatography on silica gel eluting with hexane/EtOAc (4:1),3-tert-butoxycarbonyl-7-chloro-6-[2-(4-fluorophenyl)-2-oxo-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(38 mg, 9%).

Use a method similar to the General Procedure 1-5 and purify bychromatography on silica gel eluting with DCM/2M ammonia in methanol(95:5) to obtain the free base of the title compound (23 mg, 78%). MS(ES+) m/z: 350 (M+H)⁺. Use a method similar to the General Procedure 2-2to obtain the title compound.

EXAMPLE 4787-Chloro-6-(2-hydroxyethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 347, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand methyl bromoacetate to give3-tert-butoxycarbonyl-7-chloro-6-methoxycarbonylmethylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine.

To a solution of3-tert-butoxycarbonyl-7-chloro-6-methoxycarbonylmethylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(750 mg, 1.94 mmol) in THF (25 mL) at −78° C. under nitrogen, add 1MDIBAL in toluene (5.0 mL, 5.0 mmol) dropwise with stirring. Warm to −30°C. over 1 h and quench carefully with water. Extract with EtOAc, dryover anhydrous MgSO₄, and concentrate in vacuo. Purify by chromatographyon silica gel eluting with hexane/EtOAc (4:1) to give3-tert-butoxycarbonyl-7-chloro-6-(2-hydroxy-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(651 mg, 94%).

Use a method similar to the General Procedure 1-4, using3-tert-butoxycarbonyl-7-chloro-6-(2-hydroxyethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(190 mg, 0.531 mmol) to give the title compound as a white solid (105mg, 67%). MS (ES+) m/z: 258 (M+H)⁺.

EXAMPLE 4797-Chloro-6-(3-methoxycarbonylpropylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 347, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand methyl 4-bromobutyrate to give, after deprotection by the GeneralProcedure 1-4, the title compound as a white solid. MS (ES+) m/z: 314(M+H)⁺.

EXAMPLE 4807-Chloro-6-(4-methoxycarbonyl-butylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 387 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith methyl-5-bromovalerate. Purify by preparative TLC eluting with 19:1DCM/saturated ammonia in methanol. Use a method similar to the GeneralProcedure 2-2 to give the title compound as a white solid. MS (APCI+)m/z: 328 (M+H)⁺.

EXAMPLE 4817,9-Dichloro-6-(4-methoxycarbonylbutylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Obtain the free base of the title compound as a minor product fromExample 480, after preparative TLC eluting with 19:1 DCM/saturatedammonia in methanol. Use a method similar to the General Procedure 2-2to obtain the title compound as a pale yellow solid. MS (APCI+) m/z: 362(M+H)⁺.

EXAMPLE 4827-Chloro-6-cyanomethylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

Use a method similar to the Example 387 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith bromoacetonitrile. Purify by preparative reverse phase HPLC(Column: Xterra Prep RP18 19×250 mm; Solvent A: 10 mM aqueous ammoniumcarbonate, Solvent B: acetonitrile; 30-100% B over 20 minutes; flow rate25 mL/min) to give the title compound as a white solid. MS (APCI+) m/z:253 (M+H)⁺.

EXAMPLE 4836-Cyanomethylthio-7,9-dichloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

Obtain the title compound as a minor product from Example 482, afterpreparative reverse phase HPLC (Column: Xterra Prep RP18 19×250 mm;solvent A: 10 mM aqueous ammonium carbonate, solvent B: acetonitrile;30-100% B over 20 minutes; flow rate 25 mL/min). MS (APCI+) m/z: 287(M+H)⁺.

EXAMPLE 484(±)-7-Chloro-6-(1-cyanoethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Preparation 177, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2-bromopropionitrile to give, after deprotection using a methodsimilar to the General Procedure 1-4, the title compound as a whitesolid. MS (ES+) m/z: 267 (M+H)⁺.

EXAMPLE 485(±)-7-Chloro-6-(1-cyanopropylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To a stirred solution of 1.5M lithium diisopropylamide in cyclohexane(1.37 mL, 2.05 mmol) in dry THF (5 mL) at −78° C. under dry nitrogen,add a solution of3-tert-butoxycarbonyl-7-chloro-6-cyanomethylthio-2,3,4,5-tetrahydro-1H-benzo[d]-azepine(600 mg, 1.70 mmol) in THF (5 mL) and continue stirring for 2 h. Rapidlytransfer the above solution via cannula to a solution of ethyl iodide(13.2 g, 84.9 mmol) in THF (5 mL) and continue stirring for 1 h. Quenchwith aqueous saturated ammonium chloride solution, extract three timeswith EtOAc, dry over anhydrous Na₂SO₄, and concentrate in vacuo. Purifyby chromatography on silica gel eluting with hexane/EtOAc (9:1) to give(±)-3-tert-butoxycarbonyl-7-chloro-6-(1-cyanopropylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a pale oil (350 mg, 68%). Use a method similar to the GeneralProcedure 1-4 to give the title compound as an off-white solid. MS (ES+)m/z: 281 (M+H)⁺.

EXAMPLE 4867-chloro-6-(1-cyano-1-methylethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To a stirred solution of3-tert-butoxycarbonyl-7-chloro-6-cyanomethylthio-2,3,4,5-tetrahydro-1H-benzo[d]-azepine(300 mg, 0.85 mmol) in THF (5 mL) at 0° C., add potassium tert-butoxide(480 mg, 4.26 mmol) at ambient temperature. After 15 min, add methyliodide (3.02 g, 21.31 mmol) and continue stirring overnight at ambienttemperature. Concentrate in vacuo and purify by chromatography on silicagel eluting with hexane/EtOAc (9:1) to give3-tert-butoxycarbonyl-7-chloro-6-(1-cyano-1-methyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(177 mg, 55%). MS (ES+) m/z: 282 (M+H-Boc)⁺. Use a method similar to theGeneral Procedure 1-4 to give the title compound as an off-white solid.MS (ES+) m/z: 282 (M+H)⁺.

EXAMPLE 4877-Chloro-6-(4-cyanobutylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 387 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith 5-bromovaleronitrile. Purify by preparative reverse phase HPLC(Column: Xterra Prep RP18 19×250 mm; Solvent A: 10 mM aqueous ammoniumcarbonate, Solvent B: acetonitrile; 30-100% B over 20 minutes; flow rate25 mL/min). Use a method similar to the General Procedure 2-2 to givethe title compound as an off-white solid. MS (APCI+) m/z: 295 (M+H)⁺.

EXAMPLE 4887,9-Dichloro-6-(4-cyanobutylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Obtain the free base of the title compound as a minor product fromExample 487, after preparative reverse phase HPLC (Column: Xterra PrepRP18 19×250 mm; Solvent A: 10 mM aqueous ammonium carbonate, Solvent B:acetonitrile; 30-100% B over 20 minutes; flow rate 25 mL/min). Use amethod similar to the General Procedure 2-2 to obtain the title compoundas a tan solid. MS (ES+) m/z: 329 (M+H)⁺.

EXAMPLE 4897-Chloro-6-(2-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Preparation 177, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2-(2-bromoethyl)-pyridine hydrobromide to give, after deprotectionusing a method similar to the General Procedure 1-4, the title compound.MS (ES+) m/z 319 (M+H)⁺.

EXAMPLE 4906-[3-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-propylthio]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 387, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 5-(3-bromopropyl)-3-tert-butyl-[1,2,4]oxadiazole to give, afterdeprotection using a method similar to the General Procedure 1-4, thetitle compound as a white solid. MS (APCI+) m/z 380 (M+H)⁺.

EXAMPLE 491(−)-7-Chloro-6-(tetrahydrofuran-3-ylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 332, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand (S)-toluene-4-sulfonic acid tetrahydrofuran-3-yl ester to give,after deprotection using a method similar to the General Procedure 1-4,the title compound as an off-white solid. MS (APCI+) m/z: 284 (M+H)⁺;[α]²⁰ _(D) −28.01 (c 0.5, CH₃OH). ee=97.8% [Chiral HPLC: Column: YMCODS-AQ 120 Å 4.6×50 mm [S-3 μm]; eluent: gradient from 95:5 to 5:95 A/B;solvent A: water, 0.01% HFBA, 1% isopropanol; solvent B: acetonitrile,0.01% HFBA, 1% isopropanol; flow rate 2 mL/min].

EXAMPLE 492(+)-7-Chloro-6-(tetrahydrofuran-3-ylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 332, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand (R)-toluene-4-sulfonic acid tetrahydro-furan-3-yl ester to give,after deprotection using a method similar to the General Procedure 1-4,the title compound as an off-white solid. MS (APCI+) m/z: 284 (M+H);[α]²⁰ _(D) +32.5° (c 0.5, CH₃OH); ee=95.7% [Chiral HPLC: Column: YMCODS-AQ 120 Å 4.6×50 mm [S-3 μm]; eluent: gradient from 95:5 to 5:95 A/B;solvent A: water, 0.01% HFBA, 10% isopropanol; solvent B: acetonitrile,0.01% HFBA, 1% isopropanol; flow rate 2 mL/min].

EXAMPLE 493(±)-7-Chloro-6-(tetrahydrofuran-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 330, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2-(bromomethyl)tetrahydrofuran to give, after deprotection by theGeneral Procedure 1-4, the title compound as white crystals. MS (APCI+)m/z: 298 (M+H)⁺.

EXAMPLE 494(±)-7-Chloro-6-(tetrahydropyran-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 330, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2-(bromomethyl)tetrahydropyran to give, after deprotection by theGeneral Procedure 1-4, the title compound as a white solid. MS (APCI+)m/z: 312 (M+H)⁺.

EXAMPLE 495(S)-(+)-7-Chloro-6-(5-oxo-tetrahydrofuran-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 1-4, using(S)-3-tert-butoxycarbonyl-7-chloro-6-(5-oxo-tetrahydrofuran-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give the title compound as a white solid. MS (ES+) m/z: 312 (M+H)⁺.[α]²⁰ _(D) +78° (c 0.5, CH₃OH).

EXAMPLE 4967-Chloro-6-(3-dimethylcarbamoylpropylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Treat a solution of3-tert-butoxycarbonyl-7-chloro-6-(3-methoxycarbonyl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(385 mg, 0.90 mmol) in dioxane/water (1:1, 3.5 mL) with lithiumhydroxide (43.0 mg, 1.01 mmol) at 80° C. for 1.5 h. Cool to ambienttemperature, add aqueous saturated ammonium chloride and brine, extractthree times with ethyl ether, dry over anhydrous MgSO₄, and concentratein vacuo. Dissolve the residue in DCM (3.5 mL) and add EDC (162 mg, 0.84mmol), 1-hydroxybenzotriazole (91.0 mg, 0.67 mmol), triethylamine (0.20mL, 1.35 mmol), and dimethylamine (0.700 mL, 1.35 mmol). Stir overnightat ambient temperature. Dilute with water, extract with ethyl ether, dryover anhydrous MgSO₄; and concentrate in vacuo. Purify by chromatographyon silica gel eluting with hexane/EtOAc/methanol 60:40:1 to give3-tert-butoxycarbonyl-7-chloro-6-(3-dimethylcarbamoyl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.

Dissolve3-tert-butoxycarbonyl-7-chloro-6-(3-dimethylcarbamoyl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepinein DCM (1 mL) at ambient temperature and add 4M hydrogen chloride indioxane (200 μL, 0.8 mmol). Continue stirring until TLC showsconsumption of starting material. Concentrate in vacuo, triturate theobtained solid with dry diethyl ether and dry at 50° C. under highvacuum overnight to give the title compound as a hygroscopic white solid(45.0 mg, 57%). MS (ES+) m/z: 327 (M+H)⁺.

EXAMPLE 4977-Chloro-6-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

Dissolve3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(2.0 g, 5.20 mmol) in methanol (58 mL) and add potassium hydroxide (9.36g, 167 mmol). Heat at 50° C. for 2 h. Cool to ambient temperature, addaqueous saturated ammonium chloride and water, extract three times withEtOAc, dry over anhydrous Na₂SO₄, and concentrate in vacuo to give3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.62 g, 5.20 mmol). Dissolve the crude3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.40 g, 4.46 mmol) in dry DMF (49.8 mL) and add DBU (0.80 mL, 5.35mmol) and 3-bromopropyl phthalimide (1.55 g, 5.80 mmol). Stir at ambienttemperature for 3 h. Add aqueous saturated ammonium chloride and water.Extract twice with EtOAc, dry over anhydrous Na₂SO₄, and concentrate invacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc(6:1) to give the free base of title compound (1.64 g, 74%).

Use a method similar to the General Procedure 1-5, to deprotect3-tert-butoxycarbonyl-7-chloro-6-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineand purify by preparative reverse phase HPLC to give the title compound.MS (APCI+) m/z 401 (M+H)⁺.

EXAMPLE 4986-(3-Benzoylaminopropylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

Suspend3-tert-butoxycarbonyl-7-chloro-6-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.20 g, 2.39 mmol) in ethanol (53.2 mL), add hydrazine (0.150 mL, 4.78mmol) and heat at 65° C. for 2 h. Cool to ambient temperature, filterfrom precipitate, and concentrate in vacuo to provide the6-(3-aminopropylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(861 mg, 97%). MS (APCI+) m/z: 371 (M+H)⁺.

To a solution of6-(3-aminopropylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(46.7 mg, 0.126 mmol) in dry DCM (0.5 mL) at ambient temperature undernitrogen, add triethylamine (19.3 μL, 0.139 mmol) and benzoyl chloride(16.1 μL, 0.139 mmol). Stir at ambient temperature for 2.5 h. Addaqueous saturated ammonium chloride and water, extract three times withEtOAc, dry over anhydrous Na₂SO₄, and concentrate in vacuo. Dissolve theresidue in DCM (0.16 mL), add trifluoroacetic acid (44.6 μL, 0.58 mmol)and stir for 18 h at ambient temperature. Concentrate in vacuo andpurify by preparative HPLC [Column: YMC ODS-AQ 120 Å 20×250 mm [S10-20μm); eluent: 95:5 to 5:95 A/B; solvent A: water, 0.1% TFA, 1%isopropanol; solvent B: acetonitrile, 0.05% TFA, 1% isopropanol; flowrate 20 mL/min] to give the title compound (7.0 mg, 12%). MS (APCI+) m/z375 (M+H)⁺.

EXAMPLE 4996-[3-(3-Phenylureido)-propylthio]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

Use a method similar to the Example 498, using phenyl isocyanate, togive the title compound. MS (APCI+) m/z 390 (M+H)⁺.

EXAMPLE 5007-Chloro-6-[3-(4-trifluoromethylbenzoylamino)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

To a stirred solution of 4-trifluoromethylbenzoic acid (60.0 mg, 0.316mmol) in anhydrous DMF (1.2 mL) at ambient temperature under nitrogen,add EDC (63.6 mg, 0.332 mmol), 1-hydroxybenzotriazole (44.8 mg, 0.332mmol), 4-dimethylaminopyridine (40.5 mg, 0.332 mmol) and a solution of6-(3-aminopropylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(123 mg, 0.332 mmol) in DCM (2 mL). Stir for 18 h at ambienttemperature. Add water, extract twice with EtOAc, dry over anhydrousNa₂SO₄, and concentrate in vacuo. Treat the residue with trifluoroaceticacid (0.272 mL, 0.640 mmol) in DCM (0.451 mL) at ambient temperature for18 h. Concentrate in vacuo and purify by preparative reverse phase HPLC[Column: YMC ODS-AQ 120 Å 20×250 mm [S10-20 μm]; eluent: 95:5 to 5:95A/B; solvent A: water, 0.1% TFA, 1% isopropanol; solvent B:acetonitrile, 0.05% TFA, 1% isopropanol; flow rate 20 mL/min] to givethe title compound as a white solid (31.0 mg, 18%). MS (APCI+) m/z 443(M+H)⁺.

EXAMPLE 5017-Chloro-6-[3-(4-tert-butylbenzoylamino)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

Use a method similar to the Example 500, using6-(3-aminopropylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4-tert-butyl benzoic acid to give the title compound as a whitesolid. MS (APCI+) m/z 431 (M+H)⁺.

EXAMPLE 5027-Chloro-6-(2-ethoxycarbonylamino-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

Use a method similar to the Example 497, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 3-bromoethyl phthalimide to give6-(3-aminoethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine.MS (ES+) m/z 357 (M+H)⁺.

Use a method similar to the Example 498, using6-(3-aminoethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand ethyl chloroformate to give, after deprotection using a methodsimilar to the General Procedure 1-5, the title compound as a whitesolid. MS (APCI+) m/z: 329 (M+H)⁺.

EXAMPLE 5037-Chloro-6-{2-[(pyridine-4-carbonyl)amino]-ethylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

Use a method similar to the Example 500, using6-(3-aminoethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand isonicotinic acid to give the title compound. MS (ES+) m/z: 362(M+H)⁺.

EXAMPLE 5047-Chloro-6-[2-(cyclopropanecarbonylamino)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

Use a method similar to the Example 498, using6-(3-aminoethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand cyclopropanecarbonyl chloride to give, after deprotection using amethod similar to the General Procedure 1-5, the title compound. MS(ES+) m/z: 325 (M+H)⁺.

EXAMPLE 5056-(2-Benzenesulfonylamino-ethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

Use a method similar to the Example 498, using6-(3-amino-ethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand benzenesulfonyl chloride to give, after de protection using a methodsimilar to the General Procedure 1-5, the title compound as a whitesolid. MS (APCI+) m/z: 397 (M+H)⁺.

EXAMPLE 5067-Chloro-6-(3-pyrrol-1-yl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineTrifluoroacetate

Use a method similar to the Example 497, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand N-(3-bromopropyl)pyrrole to give, after deprotection using a methodsimilar to the General Procedure 1-5, the title compound as a whitesolid. MS (ES+) m/z: 321 (M+H)⁺.

EXAMPLE 5077-Chloro-6-[2-(2,2-dimethylpropionyloxy)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To a stirred solution of3-tert-butoxycarbonyl-7-chloro-6-(2-hydroxyethylthio)-2,3,4,5-tetrahydrobenzo[d]azepine(85 mg, 0.238 mmol) in DCM (3 ml) at 0° C., add triethylamine (331 μl,2.381 mmol) followed by trimethylacetyl chloride (147 μl, 1.190 mmol).Continue stirring for 15 min, dilute with water, extract three timeswith EtOAc, dry over anhydrous Na₂SO₄, and concentrate in vacuo.Deprotection by the General Procedure 1-5, basic workup, and by theGeneral Procedure 2-2 give the title compound. MS (ES+) m/z 342 (M+H).

EXAMPLE 5087-Chloro-6-(2-cyclohexanecarbonyloxy-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 507, using cyclohexanecarbonylchloride, to give the title compound. MS (ES+) m/z 368 (M+H).

EXAMPLE 5097-Chloro-6-(3-hydroxymethylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Preparation 242, using3-tert-butoxycarbonyl-7-chloro-6-(3-hydroxymethylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give, after deprotection by the General Procedure 1-4, the titlecompound as a white solid. MS (ES+) m/z: 334 (M+H)⁺.

EXAMPLE 5107-Chloro-6-(2-hydroxymethylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Preparation 242, using3-tert-butoxycarbonyl-7-chloro-6-(2-hydroxymethylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give, after deprotection by the General Procedure 1-4, the titlecompound as a white solid. MS (ES+) m/z: 334 (M+H)⁺.

EXAMPLE 5117-Chloro-6-(4-hydroxymethylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 1-4, using3-tert-butoxycarbonyl-7-chloro-6-(4-hydroxymethylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine,to give the title compound as a white solid. MS (ES+) m/z: 334 (M+H)⁺.

EXAMPLE 5127-Chloro-6-(4-methoxymethylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

To a stirred solution of3-tert-butoxycarbonyl-7-chloro-6-(4-hydroxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(133 mg, 0.306 mmol) in anhydrous DMF (2 mL) under nitrogen, add sodiumhydride (60% dispersion, 13-15 mg, 0.375 mmol) at ambient temperatureand continue sting for 30 min. Add methyl iodide (80 □L, 1.28 mmol).After 15 min, dilute with water, extract three times with EtOAc, dryover anhydrous MgSO₄ and concentrate in vacuo. Purify by chromatographyon silica gel eluting with hexane/EtOAc (15:1) to give3-tert-butoxycarbonyl-7-chloro-6-(4-methoxymethyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a clear oil, which crystallizes on standing to a white solid (87 mg,63%), along with recovered starting material (22 mg, 17%). Use a methodsimilar to the General Procedure 1-4 to give the title compound as awhite solid. MS (ES+) m/z: 348 (M+H-Boc)⁺.

EXAMPLE 5137-Chloro-6-(3-methoxymethylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 512, using3-tert-butoxycarbonyl-7-chloro-6-(3-hydroxymethylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give the title compound as a white solid. MS (ES+) m/z: 348 (M+H).

EXAMPLE 5147-Chloro-6-(2-methoxymethylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 512, using3-tert-butoxycarbonyl-7-chloro-6-(2-hydroxymethylbenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give the title compound as a white solid. MS (ES+) m/z: 348 (M+H).

EXAMPLE 5157-Chloro-6-(2-methoxyethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepinehydrochloride

Use a method similar to the Example 512, using3-tert-butoxycarbonyl-7-chloro-6-(2-hydroxy-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine,to give the title compound as a white solid. MS (ES+) m/z: 272 (M+H).

EXAMPLE 5167-Chloro-6-(4-methoxybutylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepinehydrochloride

Use a method similar to the Example 478, using3-tert-butoxycarbonyl-7-chloro-6-(3-methoxycarbonyl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give3-tert-butoxycabonyl-7-chloro-6-(4-hydroxybutylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Use a method similar to the Example 512, using3-tert-butoxycarbonyl-7-chloro-6-(4-hydroxybutylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give the title compound as a white solid. MS (ES+) m/z: 300 (M+H)⁺.

EXAMPLE 517(±)-7-Chloro-6-(2-methoxy-1-phenylethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 512, using(±)-3-tert-butoxycarbonyl-7-chloro-6-(2-hydroxy-1-phenylethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give, after deprotection by a method similar to the General Procedure14, the title compound as an off-white solid. MS (ES+) m/z: 348 (M+H)⁺.

EXAMPLE 518(−)-7-Chloro-6-(2-methoxy-1-phenylethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Separate the enantiomers of(±)-7-chloro-6-(2-methoxy-1-phenyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineby chiral normal phase chromatography (Chiralcel OJ 8×33 cm column,eluting with 0.2% DMEA in ethanol/heptane, 40:60). Collect the secondeluting isomer and use the General Procedure 2-2 to give the titlecompound as a white solid (76 mg, 29%). MS (ES+) m/z: 349 (M+H)⁺. [α]²⁰_(D) −176° (c 0.5, CH₃OH).

EXAMPLE 5196-(4-Fluorobenzylthio)-7-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 7, using3-tert-butoxycarbonyl-6-dimethylcarbamoylthio-7-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(75 mg, 0.206 mmol) and 4-fluorobenzyl bromide (195 mg, 1.03 mmol) togive, after chromatography on silica gel eluting with hexane/EtOAc (1:0,9:1 and 4:1),3-tert-butoxycarbonyl-6-(4-fluorobenzylthio)-7-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (59 mg, 71%). MS (ES+) m/z: 302 (M+H-Boc)⁺.

Use a method similar to the General Procedure 1-4, using3-tert-butoxycarbonyl-6-(4-fluoro-benzylthio)-7-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(55 mg, 0.137 mmol) to give the title compound as a white solid (42 mg,91%). MS (ES+) m/z: 285 (M+H)⁺.

EXAMPLE 5207-Cyano-6-(4-fluorobenzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 7, using3-tert-butoxycarbonyl-7-cyano-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(123 mg, 0.33 mmol) and 4-fluorobenzyl bromide (204 mg, 1.64 mmol), togive3-tert-butoxycarbonyl-7-cyano-6-(4-fluoro-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil (118 mg, 87%).

Use a method similar to the General Procedure 14, using3-tert-butoxycarbonyl-7-cyano-6-(4-fluoro-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(118 mg, 0.286 mmol) to give, after basic work-up, the free base of thetitle compound (89 mg, 100%). MS (ES+) m/z 313 (M+H)⁺. Use a methodsimilar to the General Procedure 2-1 to give the title compound (123 mg,100%). MS (ES+) m/z 313 (M+H)⁺.

EXAMPLE 521(±)-7-Cyano-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 7, using3-tert-butoxycarbonyl-7-cyano-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(171 mg, 0.46 mmol) and (±)-1-(4-fluorophenyl)ethyl bromide (377 mg,1.85 mmol) to give, after purification by chromatography on silica gel,(±)-3-tert-butoxycarbonyl-7-cyano-6-[1-(4-fluorophenyl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil (10.3 mg, 5.3%). MS (ES+) m/z 449 (M+Na)⁺, 465(M+K)⁺.

Use a method similar to the General Procedure 1-5, using(±)-3-tert-butoxycarbonyl-7-cyano-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(10.3 mg, 0.024 mmol) to give, after basic work-up, the free base of thetitle compound (6.8 mg, 87%). MS (ES+) m/z 327 (M+H)⁺. Use a methodsimilar to the General Procedure 2-1 to give the title compound as awhite solid (9.3 mg, 87%). MS (ES+) m/z 327 (M+H)⁺.

EXAMPLE 5227-Cyano-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate, Isomer 1

Separate the two enantiomers of(±)-7-cyano-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineby chiral HPLC (Chiralpak AD-H 15 cm×4.6 mm column with a 5 μm packingsize. Elute with heptane/ethanol (95:5) containing 0.2% DEA at 0.5mL/min with an injection volume of 10.00 μL).

Subject the first eluting isomer (t_(R)=17.2 min, ee >99%) to theGeneral Procedure 2-1 to afford the title compound as a white solid. MS(ES+) m/z 327 (M+H)⁺.

EXAMPLE 5237-Bromo-6-(3-ethoxycarbonylpropylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Preparation 177, using3-tert-butoxycarbonyl-7-bromo-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand ethyl 4-bromobutyrate to give, after deprotection by a methodsimilar to the General Procedure 1-4, the title compound. MS (ES+) m/z:374 (M+H)⁺.

EXAMPLE 5247-Bromo-6-(3-dimethylcarbamoylpropylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 523, using7-bromo-3-tert-butoxycarbonyl-6-(3-ethoxycarbonylpropylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine,to give the title compound as a white solid. MS (ES+) m/z: 373 (M+H)⁺.

EXAMPLE 5257-Bromo-6-(4-oxo-4-pyrrolidin-1-yl-butylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 523, using7-bromo-3-tert-butoxycarbonyl-6-(3-ethoxycarbonylpropylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand pyrrolidine to give the title compound. MS (ES+) m/z: 397 (M+H)⁺.

EXAMPLE 5267-Bromo-6-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the Example 497 to react7-bromo-3-tert-butoxycarbonyl-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith 3-bromopropyl phthalimide. Use a method similar to the GeneralProcedure 1-4 to give the title compound as a white solid. MS (ES+) m/z445 (+H)⁺.

EXAMPLE 5276-[2-(2,2-Dimethylpropionyloxy)-ethylthio]-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

3-tert-Butoxycarbonyl-6-dimethylcarbamoylthio-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo[d]azepine:To a stirred solution of7-bromo-6-dimethylcarbamoylthio-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.383 g, 3.254 mmol), in NMP (40 ml) add sodium trifluoromethyl acetate(3.54 g, 26.03 mmol), copper(I) iodide (2.47 g, 13.0 mmol) and heat themixture at 180° C. for 4 h. Cool to ambient temperature. Dilute withEtOAc, water and remove the copper solid residue by filtration. Separatethe layers of filtrate and extract the aqueous layer three times withEtOAc. Dry over anhydrous Na₂SO₄, and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (6:1) to give thedesired intermediate as a yellow oil (882 mg, 74%).3-tert-Butoxycarbonyl-6-[2-(tert-butyl-dimethylsilanyloxy)ethylthio]-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Use a method similar to the Preparation 177, using3-tert-butoxycarbonyl-6-dimethylcarbamoylthio-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo[d]azepineand (2-bromoethoxy)-tert-butyldimethylsilane to give the desiredintermediate.3-tert-Butoxycarbonyl-6-(2-hydroxyethylthio)-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Dissolve6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylthio]-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(153 mg, 0.303 mmol) in THF (3 mL). Add 1.0 M tetrabutylammoniumfluoride in THF (600 μL, 0.606 mmol,) and stir overnight. Dilute withwater, extract three times with EtOAc, dry over anhydrous Na₂SO₄, andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (85:15) to give the desired intermediate.6-[2-(2,2-Dimethylpropionyloxy)-ethylthio]-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepinehydrochloride: Use a method similar to the Example 507, using3-tert-butoxycarbonyl-6-(2-hydroxyethylthio)-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give, after deprotection using a method similar to the GeneralProcedure 1-4, the title compound as a white solid. MS (ES+) m/z: 376(M+H)⁺.

General Procedure 8

Dissolve the appropriate bromide (2 equiv.) in isopropylamine (300-400equiv.) at room temperature, under nitrogen, then add palladium(I)bis(benzonitrile) dichloride (0.2 equiv.), triphenylphoshine (0.4equiv.) and copper(I) iodide (0.2 equiv.). Degas the solution and purgewith nitrogen, then add the appropriate alkyne (1.0 equiv.). Seal thereaction vessel, stir at room temperature for 30 min, then at 75° C. for3-4 h. Remove most of the solvent in vacuo, add diethyl ether and 2Maqueous HCl. Dry the organic layer over MgSO₄, filter and concentrate invacuo. Purify by chromatography on silica gel eluting withisohexane/EtOAc or hexane/EtOAc mixtures.

Preparation 249 2-Ethynyl-thiophene

Trimethyl-thiophen-2-ylethynyl-silane: Use a method similar to theGeneral Procedure 8 to couple 2-bromo-thiophene (0.97 nm, 10 mmol) withethynyl-trimethylsilane (2.82 mL, 20 mmol). Purify by chromatography onsilica gel eluting with isohexane to give the desired intermediate (1.46g, 81%). GC-MS m/z 180 (M⁺).2-Ethynyl-thiophene: Add a saturated solution of potassium carbonate inmethanol (7.5 mL) to trimethyl-thiophen-2-ylethynyl-silane (540 mg, 3mmol) in deoxygenated methanol (100 mL) at room temperature undernitrogen. Stir the reaction for 3.5 h, then dilute with dichloromethane(100 mL) and wash with water (3×100 mL). Remove the organic layer, dryusing an ISCO® phase separator and then concentrate in vacuo to give thetitle compound (302 mg, 93%).

Preparation 2503-tert-Butoxycarbonyl-7-chloro-6-ethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine

7-Chloro-3-(2,2,2-trifluoroacetyl)-6-trimethylsilanylethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Use a method similar to the General Procedure 3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(425 mg, 1 mmol) with 2-trimethylsilylacetylene (0.28 mL, 2 mmol).Purify by chromatography on silica gel eluting with isohexane/EtOAc(100:0 to 85:15 gradient over 40 min) to give the desired intermediate(247 mg, 81%). MS (ES+) m/z: 306 (M+H)⁺.3-tert-Butoxycarbonyl-7-chloro-6-ethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add a solution of potassium carbonate (999 mg, 7.2 mmol) in water (5 mL)to7-chloro-3-(2,2,2-trifluoroacetyl)-6-trimethylsilanylethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(180 mg, 0.48 mmol) in methanol (10 mL) and stir at room temperature,under nitrogen for 1.5 h. Add di-tert-butyl-dicarbonate (115 mg, 0.53mmol) in dichloromethane (8 mL) and stir for 3 days. Add anothersolution of di-tert-butyl-dicarbonate (115 mg, 0.53 mmol) indichloromethane (5 mL) and stir for 2 h. Add water (10 mL) anddichloromethane (10 mL) and separate the organic layer. Extract theaqueous layer with dichloromethane (3×10 mL) and combine the organiclayers. Dry using an ISCO® phase separator and concentrate. Purify bychromatography on silica gel eluting with isohexane/EtOAc (1:0 to 4:1gradient over 30 min) to give the title compound as a solid (150 mg,100%). MS (ES+) m/z: 328 (M+Na)⁺.

Preparation 251 2-Chloro-pyridazine

Add 3(2H)-pyridazinone (2 g, 22 mmol) to neat phosphorus oxychloride (4mL) in a sealed tube and heat the mixture at 80° C. with stirring for 2h. Add cautiously water (10 mL), saturated aqueous NaHCO₃ (50 mL) andsolid Na₂CO₃ until pH=9. Extract the mixture with dichloromethane (4×50mL). Dry the organic layer over Na₂SO₄, filtrate and concentrate invacuo to give the title compound as brown oil (2 g, 84%).

Preparation 252 1-tert-Butyl-3-prop-2-ynyl-imidazolidin-2-one

Dissolve 1-tert-butyl-imidazolidin-2-one (2 g, 14 mmol) in anhydrous THF(60 mL) and cool at −78° C. Slowly add n-butyllithium (6.8 mL, 17 mmol,2.5 M solution in hexanes). Stir the solution for 30 min. Rapidly addpropargyl bromide (3.2 mL, 28.2 mmol, 80% solution in toluene). Warm thesolution to room temperature while stirring overnight Concentrate thereaction mixture in vacuo and filter the residue on a short pad ofsilica gel eluting with dichloromethane/diethyl ether (1:1) to give thetitle compound as a yellow oil that solidifies on standing (1.77 g,70%). GC-MS m/z (%) 180 (M⁺, 7), 165 (100), 123 (12), 84 (17).

EXAMPLE 5287-Chloro-6-pyridin-2-ylethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(425 mg, 1 mmol) with 2-ethynyl-pyridine (0.20 mL, 2 mmol). Purify bychromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1gradient over 40 min) to give7-chloro-6-pyridin-2-ylethynyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(342 mg, 90%). MS (ES+) m/z: 379 (M+H)⁺.

Use a method similar to the General Procedure 1-2 to deprotect7-chloro-6-pyridin-2-ylethynyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(60 mg, 0.159 mmol). Purify by SCX chromatography to give the free baseof the title compound (33 mg, 73%). MS (ES+) m/z: 283 (M+H)⁺. Use amethod similar to the General Procedure 2-1 to give the title compoundas a light brown solid (45 mg, 95%). MS (ES+) m/z: 283 (M+H)⁺.

EXAMPLES 529-531

Examples 529-531 may be prepared essentially as described in Example 528by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate alkyne. Overall yields and MS (ES+) data are shownin the Table below.

Yield MS (ES+) Ex. R Compound (%) m/z 529 3-Pyridyl7-Chloro-6-pyridin-3- 78 283 ylethynyl-2,3,4,5-tetrahydro- (M + H)⁺1H-benzo[d]azepine Succinate 530 4-Pyridyl 7-Chloro-6-pyridin-4- 84 283ylethynyl-2,3,4,5-tetrahydro- (M + H)⁺ 1H-benzo[d]azepine Succinate 5312-Thiophenyl 7-Chloro-6-thiophen-2- 95 288 ylethynyl-2,3,4,5-tetrahydro-(M + H)⁺ 1H-benzo[d]azepine Succinate

EXAMPLE 5327-Chloro-6-thiazol-2-ylethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

3-tert-Butoxycarbonyl-7-chloro-6-(thiazol-2-ylethynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Use a method similar to the General Procedure 8 to couple2-bromo-thiazole (0.09 mL, 0.96 mmol) with3-tert-butoxycarbonyl-7-chloro-6-ethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(148 mg, 0.48 mmol). Purify by chromatography on silica gel eluting withisohexane/EtOAc (1:0 to 4:1 gradient over 30 min) to give the desiredintermediate (165 mg, 89%). MS (ES+) m/z: 389 (M+H)⁺.7-Chloro-6-(thiazol-2-ylethynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate: Use a method similar to the General Procedure 1-5 todeprotect3-tert-butoxycarbonyl-7-chloro-6-(thiazol-2-ylethynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(140 mg, 0.36 mmol). Elute through SCX column to give the free base ofthe title compound (89 mg, 86%). MS (ES+) m/z: 289 (M+H)⁺. Use a methodsimilar to the General Procedure 2-1 to give the title compound as alight yellow solid (125 mg, 86%). MS (ES+) m/z: 289 (M+H)⁺.

EXAMPLE 5337-Chloro-6-pyridazin-3-ylethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate

3-tert-Butoxycarbonyl-7-chloro-6-pyridazin-3-ylethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Use a method similar to the General Procedure 8 to couple2-chloro-pyridazine (98 mg, 0.86 mmol) with3-tert-butoxycarbonyl-7-chloro-6-ethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(104 mg, 0.34 mmol). Purify by chromatography on silica gel eluting withisohexane/EtOAc (1:0 to 4:1 gradient over 30 min) to give3-tert-butoxycarbonyl-7-chloro-6-pyridazin-2-ylethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(26 mg, 10%). MS (ES+) m/z: 384 (M+H)⁺.7-Chloro-6-pyridazin-3-ylethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-tartrate: Use a method similar to the General Procedure 1-5 todeprotect3-tert-butoxycarbonyl-7-chloro-6-pyridazin-2-ylethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Use a method similar to the General Procedure 2-6 to give the titlecompound as a solid (15 mg, 51%). MS (ES+) m/z: 284 (M+H)⁺.

EXAMPLE 5347-Chloro-6-(3-fluoro-phenylethynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate

Use a method similar to the General Procedure 3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(425 mg, 1 mmol) with (3-fluorophenyl)-ethyne (241 mg, 2 mmol). Purifyby chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1gradient over 40 min) to give7-chloro-6-(3-fluoro-phenylethynyl)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(247 mg, 64%). MS (ES+) m/z: 396 (M+H)⁺.

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-(3-fluoro-phenylethynyl)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(68 mg, 0.18 mmol). Purify by SCX chromatography to give the free baseof the title compound (46 mg, 85%). MS (ES+) m/z: 300 (M+H)⁺. Use amethod similar to the General Procedure 2-6 to give the title compoundas a white solid (61 mg, 94%). MS (ES+) m/z: 300 (M+H)⁺.

EXAMPLE 5357-Chloro-6-(2-fluoro-phenylethynyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(425 mg, 1 mmol) with (2-fluorophenyl)-ethyne (241 mg, 2 mmol). Purifyby chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1gradient over 40 min) to give7-chloro-6-(2-fluoro-phenylethynyl)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(262 mg, 68%). MS (ES+) m/z: 396 (M+H)⁺.

Use methods similar to the General Procedures 1-1 and 2-1 to give thetitle compound as a white solid (93%). MS (ES+) m/z: 300 (M+H)⁺.

EXAMPLE 5366-[3-(3-tert-Butyl-2-oxo-imidazolidin-1-yl)-prop-1-ynyl]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate

Use a method similar to the General Procedure 3 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(425 mg, 1 mmol) with 1-tert-butyl-3-prop-2-ynyl-imidazolidin-2-one (360mg, 2 mmol). Purify by chromatography on silica gel eluting withisohexane/EtOAc (19:1 to 3:2 gradient) to give6-[3-(3-tert-butyl-2-oxo-imidazolidin-1-yl)-prop-1-ynyl]-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(380 mg, 83%) as a yellow oil. LC-MS (ES+) m/z: 478 (M+Na)⁺, 456 (M+H)⁺,t_(R)=4.43 min.

Use a method similar to the General Procedure 1-1, but adding water (10mL) to the ammonia/methanol solution (20 mL, 7N solution), to deprotect6-[3-(3-tert-butyl-2-oxo-imidazolidin-1-yl)-prop-1-ynyl]-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(329 mg, 0.72 mmol) and give the free base of the title compound (217mg, 84%). Use a method similar to the General Procedure 2-6 to give thetitle compound as a solid (211 mg, 58% overall yield). LC-MS (ES+) m/z:360 (M+H)⁺, t_(R)=4.54 min.

Preparation 253 2,2-Difluoro-2-phenyl-ethylamine

2,2-Difluoro-2-phenyl-ethanol: Add lithium aluminum hydride (5.18 mL,5.18 mmol, 1M solution in THF) to a solution of methyldifluorophenylethanoate (0.964 g, 5.18 mmol, prepared by following theprocedure described in J. Org. Chem. 1995, 60, 5174-5179) in anhydrousTHF (10 mL) at 0° C. Stir the mixture at room temperature for 45 min.Cool to 0° C. and quench with EtOAc and then water. Separate the organicphase and extract twice the aqueous phase with EtOAc. Dry the combinedorganic extracts over Na₂SO₄, filter and concentrate in vacuo to providethe desired intermediate (0.8 g, 98%) that was used without any furtherpurification.2,2-Difluoro-2-phenyl-ethyl trifluoromethanesulfonate: Add triflicanhydride (1.28 mL, 2.14 g) dropwise to a stirred solution of2,2-difluoro-2-phenyl-ethanol (0.8 g, 5.06 mmol) and2,6-di-tert-butyl-4-methylpyridine (1.556 g, 7.59 mmol) in anhydrousdichloromethane (25 mL) at −78° C. Stir the reaction overnight while thetemperature warms up. Dilute the mixture with pentane and filter theprecipitate over Celite®b. Concentrate the filtrate in vacuo and purifythe crude mixture by chromatography on silica gel eluting with hexaneand hexane/EtOAc (95:5) to provide the title compound (946 mg, 64%).(2-Azido-1,1-difluoro-ethyl)-benzene: Heat at 60° C. a solution of2,2-difluoro-2-phenyl-ethyl trifluoromethanesulfonate (759 mg, 2.617mmol) and sodium azide (357 mg, 5.496 mmol) in anhydrous DMF (10 mL)under nitrogen for 3 h. Cool the reaction mixture to room temperature.Dilute with water and extract the aqueous phase twice with diethylether. Wash the combined organic extracts twice with ice-cold water, dryover Na₂SO₄, filter and concentrate in vacuo to provide the desiredintermediate as an oil (475 mg, 99%) that was used without any furtherpurification.2,2-Difluoro-2-phenyl-ethylamine: Dissolve(2-azido-1,1-difluoro-ethyl)-benzene (475 mg, 2.59 mmol) in EtOAc (30mL). Add 10% Pd/C and submit the mixture to hydrogenation underatmospheric pressure (balloon) for 1 h. Filter the catalyst throughCelite® and concentrate the filtrate in vacuo to provide the titlecompound as an oil (400 mg, 98%) that was used without any furtherpurification.

Preparation 254 2-Bromo-benzothiazole-6-carbonitrile

2-Oxo-2,3-dihydro-benzothiazole-6-carbonitrile: Combine6-bromobenzothiazolinone (2 g, 8.69 mmol), copper cyanide (1.3 g, 1.48mmol), anhydrous DMF (5 mL) and heat at reflux for 15 h. Add water (20mL) and sodium cyanide (1.4 g, 27.7 mmol) at 100° C. Cool the reactionmixture to room temperature and stir for 2 h. Extract the reactionmixture with EtOAc (5×30 mL) at 70° C. Combine the organic layers, washwith water (3×40 mL) and dry over anhydrous Na₂SO₄. Concentrate in vacuoto obtain the desired intermediate as a yellow solid (2 g, 87%). GC-MSm/z: 176 (M⁺).2-Bromo-benzothiazole-6-carbonitrile: Combine2-oxo-2,3-dihydro-benzothiazole-6-carbonitrile (1.1 g, 6.24 mmol),tetrabutylammonium bromide (3 g, 9.36 mmol), phosphorus pentoxide (2.7g, 18.7 mmol), anhydrous toluene (40 mL) and heat at reflux for 2.5 h.Cool the reaction mixture to room temperature. Decant the toluene layerand wash with saturated aqueous NaHCO₃ (3×10 mL). Concentrate theorganic phase in vacuo and purify the residue by chromatography onsilica gel eluting with hexane/EtOAc (1:0 to 4:1 gradient) to obtain thetitle compound as a colorless oil (0.9 g, 61%). GC-MS m/z: 239 (M⁺).

Preparation 255 6-Aminomethyl-2-cyclohexylmethyl-benzothiazole

2-Cyclohexylmethyl-benzothiazole-6-carbonitrile: Place2-bromo-benzothiazole-6-carbonitrile (0.2 g, 0.96 mmol), anhydrous THF(3 mL), 1-methyl-2-pyrrolidinone (3 mL), tetrabutylammonium iodide (1.1g, 2.89 mmol), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.09mmol) and [1,1′-bis(diphenylphosphino)ferrocine]dichloropalladium (II)(11 mg, 0.09 mmol) in a flask. Add 0.5M cyclohexylmethylzinc bromide inTHF (3.8 mL, 1.92 mmol) to the mixture, degas 3 times by partiallyevacuating the atmosphere and flushing with nitrogen and stir thereaction mixture at 80° C. for 2 h. Cool the reaction mixture to roomtemperature, dilute with EtOAc (10 mL) and wash with brine (10 mL). Drythe organic layer over anhydrous Na₂SO₄, filter and concentrate invacuo. Purity the residue by chromatography on silica gel elutingsequentially with hexane/EtOAc (1:0 to 4:1 gradient) to obtain thedesired intermediate as a yellow solid (140 mg, 57%). GC-MS m/z: 256(M⁺).6-Aminomethyl-2-cyclohexylmethyl-benzothiazole: Dissolve2-cyclohexylmethyl-benzothiazole-6-carbonitrile (0.2 g, 0.55 mmol) inanhydrous THF (2 mL) and add slowly 1M lithium aluminum hydride in THF(0.82 mL, 0.82 mmol) at room temperature. Stir the reaction mixture atroom temperature for 0.5 h. Quench the reaction mixture with water untila granular precipitate starts to form and filter through a pad ofCelite®. Evaporate the solvent and purify the residue by SCXchromatography to obtain the title compound as a yellow oil (0.1 g,92%). MS (ES+) m/z: 260 (M+H)⁺.

Preparation 256 6-Aminomethyl-2-phenyl-benzothiazole

6-Methyl-2-phenyl-benzothiazole: Heat at reflux a mixture of2-amino-5-methyl-benzenethiol zinc salt (13.5 g, 24.9 mmol, prepared byfollowing the procedure described in Helv. Chim. Acta 1974, 57, 2664)and ethyl benzimidate hydrochloride (9.23 g, 49.7 mmol) in methanol (240mL) for 9 h. Filter the mixture, evaporate the filtrate and purify theresidue by chromatography on silica gel eluting with hexane/EtOAc (100:0to 85:15 gradient) to obtain the desired intermediate (5.7 g, 51%). MS(EI) m/z: 225 (M⁺).6-Bromomethyl-2-phenyl-benzothiazole: Heat5-methyl-2-phenyl-benzothiazole (5.7 g, 25.3 mmol) and NBS (4.73 g, 26.6mmol) in carbon tetrachloride (140 mL) at 80° C. for 3 h. Cool themixture, double the volume with dichloromethane, filter and concentratein vacuo. Purify the crude mixture by chromatography on silica geleluting with hexane/EtOAc (1:0 to 7:3 gradient) to obtain the desiredintermediate (3.1 g, 40%). MS (FI) m/z: 303, 305 (M⁺).6-Aminomethyl-2-phenyl-benzothiazole: Add6-bromomethyl-2-phenyl-benzothiazole (2 g, 6.57 mmol) as a suspension inmethanol (100 mL) to 7M ammonia in methanol (400 mL) at 0° C. over 10min and then stir for 3 h at room temperature. Concentrate in vacuo andpurify the crude mixture by chromatography on silica gel eluting withdichloromethane/methanol (1:0 to 3:1) to obtain the title compound (1.2g, 76%). MS (ES+) m/z: 241 (M+H⁺).

Preparation 257 5-Aminomethyl-2-isobutyl-benzothiazole

2-Oxo-2,3-dihydro-benzothiazole-5-carbonitrile: Heat a mixture of5-chloro-3H-benzothiazol-2-one (9.3 g, 50 mmol), nickel(II) bromide(10.9 g, 50 mmol) and sodium cyanide (4.91 g, 100 mmol) in1-methyl-pyrrolidinone (100 mL) in a microwave reactor 5 to 200° C. over15 min and hold 1 h. Filter the cooled mixture through a glass frit, adddiethyl ether and brine and filter again. Wash the organic phase withbrine three times and concentrate in vacuo. Pass the residue through aplug of silica gel eluting with hexane/EtOAc (2:1) and thendichloromethane/methanol (9:1) to obtain the desired intermediate (3.2g, 36%). MS (ES+) m/z: 177 (M+H)⁺.2-Bromo-benzothiazole-5-carbonitrile: Heat2-oxo-2,3-dihydro-benzothiazole-5-carbonitrile (3.2 g, 18.2 mmol) intoluene (120 mL) with tetrabutylammonium bromide (8.78 g, 27.2 mmol) andphosphorus pentoxide (7.73 g, 54.5 mmol) for 3 h at reflux. Cool themixture, decant the solution from the reaction residue and partitionbetween diethyl ether and brine. Add water and dichloromethane to thereaction residue and reflux for 20 min. Wash the dichloromethane layerwith saturated aqueous NaHCO₃ and brine, and combine with the etherwashing. Dry the organic mixture over Na₂SO₄ and concentrate in vacuo.Purify the crude mixture by chromatography on silica gel eluting withhexane/EtOAc (1:0 to 3:7 gradient) to give the desired intermediate(0.85 g, 20%). MS (EI) m/z: 238, 240 (M⁺).2-Isobuty-benzothiazole-5-carbonitrile: Heat2-bromo-benzothiazole-5-carbonitrile (0.3 g, 1.26 mmol) in1-methyl-pyrrolidinone (4.2 mL) with 2-methylpropylzinc bromide (5 mL,2.5 mmol, 0.5M solution in THF), N-methylimidazole (0.15 g, 1.88 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexwith dichloromethane (1:1) (20.5 mg, 0.025 mmol) at 80° C. for 3 h. Coolthe mixture and partition between diethyl ether and brine. Dry theorganic layer over Na₂SO₄ and concentrate in vacuo. Purify the crudemixture by chromatography on silica gel eluting with hexane/EtOAc (1:0to 1:1 gradient) to give the desired intermediate (113 mg, 42%). MS (EI)m/z: 216 (M⁺).5-Aminomethyl-2-isobutyl-benzothiazole: Add lithium aluminum hydride(0.78 mL, 0.78 mmol, 1M solution in THF) to2-isobutyl-benzothiazole-5-carbonitrile (113 mg, 0.52 mmol) in THF (5mL) and stir for 4 h at room temperature. Add water (0.27 mL), 2N sodiumhydroxide (0.27 mL) and water (0.37 mL). Filter the precipitate and washthe filtrate with brine. Dry over Na₂SO₄ and concentrate in vacuo.Purify the crude mixture by chromatography on silica gel eluting withhexane/EtOAc (1:1) and then 1M ammonia in methanol/dichloromethane(1:9). Purify the polar fraction by SCX chromatography to give the titlecompound (63 mg, 55%). MS (ES+) m/z: 221 (M+HE).

Preparation 258 6-Aminomethyl-benzo[1,2,3]thiadiazole

6-Hydroxymethyl-benzo[1,2,3]thiadiazole: Add sodium borohydride (1.35 g,36 mmol) in five portions over 4 h to a solution ofbenzo[1,2,3]thiadiazole-6-carboxylic acid methyl ester (0.35 g, 1.8mmol, prepared by following the procedure described in J. HeterocyclicChem. 1972, 1149) in methanol (18 mL) at 0° C. Add acetone to quench andevaporate the mixture onto silica gel. Purify the residue bychromatography on silica gel eluting with hexane/EtOAc (1:0 to 2:3gradient) to give the desired intermediate (133 mg, 45%). MS (GCMS) m/z:166 M⁺.6-Aminomethyl-benzo[1,2,3]thiadiazole: Stir6-hydroxymethyl-benzo[1,2,3]thiadiazole (133 mg, 0.8 mmol) inthionylchloride (5 mL) for 3 h at room temperature. Evaporate themixture then add 7M ammonia in methanol (10 mL) and stir at roomtemperature in a sealed tube for 48 h. Evaporate the mixture and purifythe residue by SCX chromatography to give the title compound (115 mg,87%). MS (ES+) m/z: 166 (M+H)⁺.

Preparation 259 6-Aminomethyl-3-phenyl-benzothiophene

2-(3-Bromo-phenylthio)-1-phenyl-ethanone: Add potassium hydroxide (4.89g, 87.3 mmol) and 2-bromoacetophenone (15.8 g, 79.3 mmol) to a solutionof 3-bromobenzenethiol (15 g, 79.3 mmol) in ethanol (200 mL, 70% inwater) at 0° C. After stirring 16 h, add water to precipitate a yellowsolid. Filter to obtain the desired intermediate (24.6 g, 100%).6-Bromo-3-phenylbenzothiophene: Heat2-(3-bromo-phenylthio)-1-phenyl-ethanone (4 g, 13 mmol) inpolyphosphoric acid (4 g) at 80° C. for 4 h. Add EtOAc and water to themixture and wash with saturated aqueous NaHCO₃ and brine. Dry theorganic layer over Na₂SO₄, filter and concentrate in vacuo. Slurry theresidue in hexane and purify by chromatography on silica gel elutingwith hexane to give the desired intermediate that is used withoutfurther purification (2.7 g, 72%). MS (GCMS) m/z: 289 M⁺.6-Cyano-3-phenylbenzothiophene: Combine 6-bromo-3-phenylbenzothiophene(0.5 g, 1.73 mmol) and copper cyanide (0.56 g, 6.23 mmol) and reflux 3 hin 1-methyl-2-pyrrolidinone (1.73 mL). Add ferric chloride (2.11 g, 7.79mmol) in concentrated HCl (1.73 mL) and stir 1.5 h. Cool the mixture andpartition between diethyl ether and brine. Dry the organic layer overNa₂SO₄, filter and evaporate onto silica gel. Purify the residue bychromatography on silica gel eluting with hexane/EtOAc (1:0 to 3:2gradient) to give the desired intermediate that is used withoutfurther-purification (0.27 g, 67%). MS (GCMS) m/z: 235 M⁺.6-Aminomethyl-3-phenyl-benzothiophene: Dissolve6-cyano-3-phenylbenzothiophene (0.27 g, 1.16 mmol) in anhydrous THF (6mL) and add lithium aluminum hydride (3.45 mL, 1M solution in THF) at 0°C. After 2 h, add water (0.86 mL), 2N aqueous NaOH (0.86 mL) and water(1.24 mL). Filter off the solids and evaporate the residue. Purify byprep HPLC (Zorbax SB-Phenyl column 21.2×250 mm, 5% to 50% acetonitrilein 0.1% TFA-water solution) and obtain the free base by SCXchromatography to give the title compound that is used without furtherpurification (187 mg, 68%). MS (ES+) m/z: 223 (M-NH₂)⁺.

Preparation 260 4-(Difluoro-phenyl-methyl)-benzylamine

Combine 4-(difluoro-phenyl-methyl)-toluene (0.29 g, 1.35 mmol, preparedby following the procedure described in Tetrahedron 1996, 52, 9), NBS(0.26 g, 1.48 mmol), and AIBN (6 mg, 0.03 mmol) in carbon tetrachloride(8 mL) and heat at 80° C. for 16 h. Evaporate the mixture and pass theresidue through a pad of silica gel washing with hexane and evaporatethe filtrate. Dissolve the residue in methanol and add dropwise to 7Mammonia in methanol (100 mL) at 0° C. After 4.5 h, evaporate the mixtureand isolate the amine by SCX chromatography (0.1 g, 32%). MS (ES+) m/z:234 (M+H)⁺.

Preparation 261 4-(3,3-Dimethyl-butyryl)-benzylamine

3,3,4′-Trimethylbutyrophenone: Add slowly tert-butylacetyl chloride (2g, 14.858 mmol) to an ice-cold stirred solution of aluminum trichloride(2.972 g, 22.28 mmol) in anhydrous toluene (40 mL). Stir the reactionmixture at ambient temperature overnight. Add slowly ice-cold water andextract the mixture twice with EtOAc. Dry the combined organic extractsover Na₂SO₄, filter and concentrate in vacuo to give the desiredintermediate (2.82 g, 100%) that was used without any furtherpurification. GC-MS m/z: 190 (M⁺).4-(3,3-Dimethyl-butyryl)-benzyl bromide: Heat a mixture of3,3,4′-trimethylbutyrophenone (2 g, 10.52 mmol), NBS (2.061 g, 11.57mmol), and AIBN (43 mg, 0.263 mmol) in carbon tetrachloride (60 mL) for14 h at reflux. Cool the reaction, mixture to ambient temperature andwash sequentially with water, 1M aqueous HCl, 5% aqueous NaHCO₃ andbrine. Concentrate the organic layer in vacuo to provide the desiredintermediate as oil (2.54 g, 90%) that was used without any furtherpurification.2-[4-(3,3-Dimethyl-butyryl)-benzyl]-isoindole-1,3-dione: Add4-(3,3-dimethyl-butyryl)-benzyl bromide (1 g, 3.731 mmol) to a stirredsuspension of potassium phthalimide (0.705 g, 3.805 mmol) in anhydrousDMF (20 mL). Stir the mixture overnight at room temperature. Dilute withEtOAc and wash twice with ice-cold water. Dry the organic layer overNa₂SO₄, filter and concentrate in vacuo. Purify the crude mixture bychromatography on silica gel eluting sequentially with hexane andhexane/EtOAc (19:1, 4:1) to provide the desired intermediate as oil(1.24 g, 100%).4-(3,3-Dimethyl-butyryl)-benzylamine: Add hydrazine hydrate (0.189 mL,3.913 mmol) to a stirred suspension of2-[4-(3,3-dimethyl-butyryl)-benzyl]-isoindole-1,3-dione (875 mg, 2.609mmol) in methanol (15 mL). Heat the mixture to reflux overnight. Coolthe mixture to room temperature and concentrate in vacuo. Partition theresidue between EtOAc and 5N aqueous HCl and wash the acidic aqueousphase again with 5N aqueous HCl. Basify with 5N aqueous NaOH to pH 12.Extract the basic aqueous solution three times with chloroform. Dry thecombined organic extracts over Na₂SO₄, filter and concentrate in vacuoto give the title compound as a yellow oil (411 mg, 77%) that was usedwithout any further purification.

Preparation 262 4-(3,3-Dimethyl-butyryl)-3-fluoro-benzylamine

4-Azidomethyl-1-bromo-2-fluoro-benzene: Add sodium azide (2.912 g, 44.8mmol) to a solution of 4-bromo-3-fluorobenzyl bromide (6 g, 22.4 mmol)in anhydrous DM (127 mL) at room temperature under nitrogen. Heat themixture at 90° C. for 1 h. Concentrate in vacuo and partition theresidue between water and EtOAc. Extract the aqueous phase twice withEtOAc. Wash the combined organics extracts with iced-water. Dry theorganic layer over Na₂SO₄, filter and concentrate in vacuo to obtain thedesired intermediate as a solid (4.92 g, 96%).4-Bromo-N-(tert-butoxycarbonyl)-3-fluoro-benzylamine: Add 10% Pd/C (492mg) and di-tert-butyl-dicarbonate (4.668 g, 21.4 mmol) to a solution of4-azidomethyl-1-bromo-2-fluoro-benzene (4.92 g, 21.4 mmol) in ethanol(90 mL) and submit the mixture to hydrogenation at atmospheric pressureovernight. Filter the reaction mixture over Celite® and concentrate invacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc(85:15) to obtain the desired intermediate as a solid (1.55 g, 25%).N-(tert-Butoxycarbonyl)-3-fluoro-4-(1-hydroxy-3,3-dimethyl-butyl)-benzylamine:Add butyllithium (7.3 mL, 11.7 mmol) to a solution of4-bromo-N-(tert-butoxycarbonyl)-3-fluoro-benzylamine (1.55 g, 5.1 mmol)in diethyl ether (54 mL) at −78° C. under nitrogen and stir for 30 min.Add 3,3-dimethylbutyraldehyde (562 mg, 0.7 mL, 5.6 mmol), stir for 30min at −78° C. and then warm to room temperature. Add water and extracttwice the aqueous phase with EtOAc. Dry the combined organic extractsover Na₂SO₄, filter and concentrate in vacuo. Purify by chromatographyon silica gel eluting with hexane/EtOAc (85:15) to obtain the desiredintermediate as a yellow oil (394 mg, 24%).N-(tert-Butoxycarbonyl)-4-(3,3-dimethyl-butyryl)-3-fluoro-benzylamine:Add manganese dioxide (1.132 g, 13 mmol) to a solution ofN-(tert-butoxycarbonyl)-3-fluoro-4-(1-hydroxy-3,3-dimethyl-butyl)-benzylamine(283 mg, 0.87 mmol) in anhydrous 1,4-dioxane (11.5 mL) at roomtemperature. Heat the reaction mixture at 70° C. overnight. Filter thereaction mixture over Celite® and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc (4:1) to obtainthe desired intermediate as an oil (216 mg, 77%).4-(3,3-Dimethyl-butyryl)-3-fluoro-benzylamine: Add 4N hydrogen chloridein dioxane (2.7 mL, 10.8 mmol) to a solution ofN-(tert-butoxycarbonyl)-4-(3,3-dimethyl-butyryl)-3-fluoro-benzylamine(296 mg, 0.92 mmol) in dichloromethane (11 mL) and stir for 4 h.Concentrate in vacuo and wash the solid obtained with diethyl ether.Suspend the solid in saturated aqueous NaHCO₃ and stir for 30 min.Extract twice with dichloromethane. Dry the combined organic extractsover Na₂SO₄, filter and concentrate in vacuo to obtain the titlecompound as an oil (175 mg, 82%).

Preparation 263 4-(3,3-Dimethyl-butyryl)-2-fluoro-benzylamine

4-Bromo-N-(tert-butoxycarbonyl)-2-fluoro-benzylamine: Add triethylamine(6.334 g, 8.8 mL, 52.6 mmol) and di-tert-butyl-dicarbonate (4.54 g, 20.8mmol) to a solution of 4-bromo-2-fluoro-benzylamine hydrochloride (5 g,20.8 mmol) in dichloromethane (254 mL) and stir overnight. Wash theorganic layer with water and then extract back the aqueous phase withdichloromethane. Dry the combined organic extracts over Na₂SO₄, filterand concentrate in vacuo to obtain the desired intermediate as a whitesolid (6.11 g, 97%).N-(tert-Butoxycarbonyl)-2-fluoro-4-(1-hydroxy-3,3-dimethyl-butyl)-benzylamine:Add butyllithium (14.2 mL, 22.7 mmol) to a solution of4-bromo-N-(tert-butoxycarbonyl)-2-fluoro-benzylamine (3 g, 9.9 mmol) indiethyl ether (105 mL) at −78° C. under nitrogen and stir for 30 min.Add 3,3-dimethylbutyraldehyde (1.086 g, 1.4 mL, 10.8 mmol), stir for 30min at −78° C. and then warm to room temperature. Add water and extracttwice the aqueous phase with EtOAc. Dry the combined organic extractsover Na₂SO₄, filter and concentrate in vacuo. Purify by chromatographyon silica gel eluting with hexane/EtOAc (85:15) to obtain the desiredintermediate as a yellow oil (1.179 g, 37%).N-(tert-Butoxycarbonyl)-4-(3,3-dimethyl-butyryl)-2-fluoro-benzylamine:Add manganese dioxide (4.4 g, 50.6 mmol) to a solution ofN-(tert-butoxycarbonyl)-2-fluoro-4-(1-hydroxy-3,3-dimethyl-butyl)-benzylamine(1.1 g, 3.38 mmol) in anhydrous 1,4-dioxane (45 mL) at room temperature.Heat the reaction mixture at 70° C. overnight. Filter the reactionmixture over Celite® and concentrate in vacuo. Purify by chromatographyon silica gel eluting with hexane/EtOAc (9:1) to obtain the desiredintermediate as an oil (980 mg, 90%).4-(3,3-Dimethyl-butyryl)-2-fluoro-benzylamine: Add 4N hydrogen chloridein dioxane (5.5 mL, 22 mmol) to a solution ofN-(tert-butoxycarbonyl)-4-(3,3-dimethyl-butyryl)-2-fluoro-benzylamine(600 mg, 1.85 mmol) in dichloromethane (22 mL) and stir for 6.5 h.Concentrate in vacuo and wash the solid obtained with diethyl ether.Suspend the solid into saturated aqueous NaHCO₃ and stir for 30 min.Extract the aqueous phase twice with EtOAc. Dry the combined organicextracts over Na₂SO₄, filter and concentrate in vacuo to obtain thetitle compound as an oil (420 mg, 99%).

Preparation 264 3-Chloro-4-(3,3,4-dimethyl-butyryl)-benzylamine

4-Bromo-3-chloro-benzyl bromide: Add NBS (5.266 g, 23.9 mmol) andbenzoyl peroxide (49 mg, 0.2 mmol) to a solution of4-bromo-3-chlorotoluene (4.925 g, 23.9 mmol) in carbon tetrachloride (49mL) and heat overnight at 90° C. Cool to 0° C. and filter the mixture.Concentrate the filtrate in vacuo to obtain the desired intermediate asa yellow oil (5.807 g, 85%).4-Bromo-3-chloro-N-(di-tert-butoxycarbonyl)-benzylamine: Add sodiumhydride (382 mg, 15.9 mmol) to a solution ofdi-tert-butyl-iminodicarboxylate (2.533 g, 11.7 mmol) in anhydrous DMF(15 mL) at room temperature under nitrogen and stir for 15 min. Then adda solution of 4-bromo-3-chloro-benzyl bromide (3 g, 10.6 mmol) inanhydrous DMF (5 mL) and stir for 1 h. Add water and extract the aqueousphase twice with EtOAc. Wash the combined organic extracts withiced-water. Dry the organic layer over Na₂SO₄, filter and concentrate invacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc(4:1) to obtain the desired intermediate (2.783 g, 62%).4-Bromo-3-chloro-N-(tert-butoxycarbonyl)-benzylamine: Add a solution ofsodium hydroxide (264 mg, 6.6 mmol) in methanol (23.5 mL) to a solutionof 4-bromo-3-chloro-N-(di-tert-butoxycarbonyl)-benzylamine (2.783 g, 6.6mmol) in THF (11.7 mL) and stir overnight Concentrate in vacuo. Addwater and filter the precipitate formed to obtain the desiredintermediate as a white solid (1.823 g, 86%).N-(tert-Butoxycarbonyl-3-chloro-4-(1-hydroxy-3,3-dimethyl-butyl)-benzylamine:Add butyllithium (8-2 mL, 13.1 mmol) to a solution of4-bromo-3-chloro-N-(tert-butoxycarbonyl)-benzylamine (1.823 g, 5.7 mmol)in diethyl ether (46 mL) at −78° C. under nitrogen and stir for 30 min.Add 3,3-dimethylbutyraldehyde (1.427 g, 1.7 mL, 14.3 mmol), stir for 30min at −78° C. and then warm to room temperature. Add water and extracttwice the aqueous phase with EtOAc. Dry the combined organic extractsover Na₂SO₄, filter and concentrate in vacuo. Purify by chromatographyon silica gel eluting with hexane/EtOAc (4:1) to obtain the desiredintermediate as a yellow oil (274 mg, 14%).N-(tert-Butoxycarbonyl)-3-chloro-4-(3,3-dimethyl-butyryl)-benzylamine:Add manganese dioxide (1.096 g, 12.6 mmol) to a solution ofN-(tert-butoxycarbonyl)-3-chloro-4-(1-hydroxy-3,3-dimethyl-butyl)-benzylamine(274 mg, 0.8 mmol) in anhydrous 1,4-dioxane (11.5 mL) at roomtemperature. Heat the mixture at 70° C. overnight. Filter the reactionmixture over Celite® and concentrate in vacuo. Purify by chromatographyon silica gel eluting with hexane/EtOAc (4:1) to obtain the desiredintermediate as a yellow oil (175 mg, 64%).3-Chloro-4-(3,3-dimethyl-butyryl)-benzylamine: Add 4N hydrogen chloridein dioxane (0.9 mL, 3.6 mmol) to a solution ofN-(tert-butoxycarbonyl)-3-chloro-4-(3,3-dimethyl-butyryl)-benzylamine(100 mg, 0.3 mmol) in dichloromethane (6 mL) and stir overnight.Concentrate in vacuo and wash the solid obtained with diethyl ether.Suspend the solid into saturated aqueous NaHCO₃ and stir for 30 min.Extract twice with dichloromethane. Dry the combined organic extractsover Na₂SO₄, filter and concentrate in vacuo to obtain the titlecompound as a yellow oil (66 mg, 92%).

Preparation 265 2-Chloro-4-(3,3-dimethyl-butyryl)-benzylamine

4-Bromo-2-chloro-benzyl bromide: Add NBS (13.171 g, 74 mmol) and benzoylperoxide (152 mg, 0.63 mmol) to a solution of 4-bromo-2-chlorotoluene(15.2 g, 74 mmol) in carbon tetrachloride (152 mL) and stir for 6 daysat 90° C. Cool to 0° C., filter the mixture and concentrate the filtratein vacuo. Purify by chromatography on silica gel eluting withhexane/EtOAc (99:1) to obtain the desired intermediate as a yellow oil(12.7 g, 61%).4-Bromo-2-chloro-N-di-(tert-butoxycarbonyl)-benzylamine: Add sodiumhydride (382 mg, 15.9 mmol) to a solution ofdi-tert-butyl-iminodicarboxylate (2.533 g, 11.7 mmol) in anhydrous DMF(15 mL) at room temperature under nitrogen and stir for 15 min. Then adda solution of 4-bromo-2-chloro-benzyl bromide (3 g, 10.6 mmol) inanhydrous DMF (5 mL) and stir for 1 h. Add water and extract the aqueousphase twice with EtOAc. Wash the combined organic extracts withiced-water. Dry the organic layer over Na₂SO₄, filter and concentrate invacuo. Purify by chromatography on silica gel eluting sequentially withhexane and hexane/EtOAc (4:1) to obtain the desired intermediate (4.2 g,94%).4-Bromo-N-(tert-butoxycarbonyl)-2-chloro-benzylamine: Add a solution ofsodium hydroxide (399 mg, 9.98 mmol) in methanol (35.5 mL) to a solutionof 4-bromo-2-chloro-N-di-(tert-butoxycarbonyl)-benzylamine (4.2 g, 9.98mmol) in THF (17.7 mL) and stir overnight Concentrate in vacuo andpartition the residue between water and EtOAc. Extract the aqueous phasetwice with EtOAc. Dry the combined organic extracts over Na₂SO₄, filterand concentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (4:1) to obtain the desired intermediate (2.625 g,82%).N-(tert-Butoxycarbonyl)-2-chloro-4-(1-hydroxy-3,3-dimethyl-butyl)-benzylamine:Add butyllithium (11.7 mL, 18.65 mmol) to a solution of4-bromo-N-(tert-butoxycarbonyl)-2-chloro-benzylamine (2.601 g, 8.11mmol) in diethyl ether (86 mL) at −78° C. under nitrogen and stir for 2h. Add 3,3-dimethylbutyraldehyde (1.868 g, 2.3 mL, 18.65 mmol), stir for30 min at −78° C. and then warm to room temperature. Add water andextract twice the aqueous phase with EtOAc. Dry the combined organicextracts over Na₂SO₄, filter and concentrate in vacuo. Purify bychromatography on silica gel eluting hexane/EtOAc (85:15) to obtain thedesired intermediate as a yellow oil (1.825 mg, 66%).N-(tert-Butoxycarbonyl)-2-chloro-4-(3,3-dimethyl-butyryl)-benzylamine:Add manganese dioxide (7.276 g, 83.7 mmol) to a solution ofN-(tert-butoxycarbonyl)-2-chloro-4-(1-hydroxy-3,3-dimethyl-butyl)-benzylamine(1.819 g, 5.3 mmol) in anhydrous 1,4-dioxane (75 mL) at roomtemperature. Heat the mixture at 70° C. overnight. Filter the reactionmixture over Celite® and concentrate in vacuo. Purify by chromatographyon silica gel eluting with hexane/EtOAc (85:15) to obtain the desiredintermediate as a yellow oil (1.362 g, 76%).2-Chloro-4-(3,3-dimethyl-butyryl)-benzylamine: Add 4N hydrogen chloridein dioxane (6 mL, 24 mmol) to a solution ofN-(tert-butoxycarbonyl)-2-chloro-4-(3,3-dimethyl-butyryl)-benzylamine(700 mg, 2.06 mmol) in dichloromethane (25 mL) and stir overnight.Concentrate in vacuo and wash the solid obtained with diethyl ether.Suspend the solid into saturated aqueous NaHCO₃ and stir for 30 min.Extract twice with dichloromethane. Dry the combined organic extractsover Na₂SO₄, filter and concentrate in vacuo to obtain the titlecompound as a yellow oil (477 mg, 97%).

Preparation 2664-[2-(3,3-Dimethyl-butyl)-[1,3]dioxolan-2-yl]-benzylamine

4-(4,4-Dimethyl-pentanoyl)-dibenzonitrile: Keep Mg turnings (402 mg,15.251 mmol) in vacuo in a two-neck round bottom flask for 2 h. Purgethe flask with nitrogen/vacuo several times. Add a couple crystals ofiodine, anhydrous THF (60 mL) and 3,3-dimethyl-bromobutane (0.8 mL, 5.59mmol) slowly (exothermic reaction observed). Add dropwise the remaining3,3-dimethyl-bromobutane (1.6 mL, 11.18 mmol) and reflux the mixtureovernight Add some additional 3,3-dimethyl-bromobutane (0.24 mL, 1.67mmol) and reflux for 30 min. Cool the mixture to −10° C. and add asolution of 4-cyanobenzaldehyde (4 g, 30.502 mmol) in anhydrous THF (40mL). Warm the flask gradually to room temperature overnight. Quench themixture with 0.1M aqueous HCl (100 mL) and extract twice with EtOAc. Drythe combined organic extracts over Na₂SO₄, filter and concentrate invacuo. Purify the crude mixture by chromatography on silica gel elutingwith hexane/EtOAc (19:1) to give the desired intermediate as an oil(0.752 g, 23%).4-[2-(3,3-Dimethyl-butyl)-[1,3]dioxolan-2-yl]-benzonitrile: Dissolve4-(4,4-dimethyl-pentanoyl)-benzonitrile (275 mg, 1.28 mmol) in toluene(10 mL). Add ethylene glycol (0.35 mL, 6.4 mmol) and p-toluenesulfonicacid monohydrate (24 mg, 0.128 mmol). Heat the mixture at 135° C. in aDean-Stark for 2 h and then at 120° C. overnight. Cool the mixture toroom temperature, dilute with EtOAc and wash with saturated aqueousNaHCO₃. Dry the organic phase over MgSO₄, filter and concentrate invacuo. Purify the crude mixture by chromatography on basic aluminaeluting with hexane and hexane/EtOAc (19:1) to give the desiredintermediate as an oil (0.272 g, 82%).4-[2-(3,3-Dimethyl-butyl)-[1,3]dioxolan-2-yl]-benzylamine: Dissolve4-[2-(3,3-dimethyl-butyl)-[1,3]dioxolan-2-yl]-benzonitrile (271 mg,1.046 mmol) in anhydrous THF (10 mL). Add under nitrogen 1M lithiumaluminum hydride in THF (2.1 mL, 2.1 mmol) at 0° C. and stir the mixtureat room temperature for 2 h. Cool to 0° C., add water and extract theaqueous phase twice with EtOAc. Dry the combined organic extracts overMgSO₄, filter and concentrate in vacuo to obtain the desiredintermediate as an oil (0.263 mg) that was used without any furtherpurification.

Preparation 267 4-Cyclohexanecarbonyl-benzylamine

Cyclohexyl-p-tolyl-methanone: Dissolve cyclohexanecarbonyl chloride (2g, 13.6 mmol) in anhydrous toluene (30 mL). Cool the solution to 0° C.,add aluminum trichloride (2.72 g, 20.46 mmol) in three portions and stirthe reaction mixture at ambient temperature overnight Cool to 0° C., addslowly water and extract the mixture with EtOAc. Dry the organic layerover Na₂SO₄, filter and concentrate in vacuo. Purify the crude mixtureby chromatography on silica gel eluting with hexane and hexane/EtOAc(19:1) to give the desired intermediate (2.75 g, 100%).4-(Cyclohexanecarbonyl)-benzyl bromide: Heat a mixture ofcyclohexyl-p-tolyl-methanone (1 g, 4.943 mmol), NBS (1.232 g, 6.92mmol), and AIBN (41 mg, 0.247 mmol) in carbon tetrachloride (80 mL) for14 h at reflux. Add additional NBS (264 mg) and AIBN (19 mg) and refluxthe mixture for 4 h. Cool the reaction mixture to ambient temperatureand filter. Concentrate the filtrate in vacuo to provide the desiredintermediate as oil (1.132 g, 81%) that was used without any furtherpurification.(4-Azidomethyl-phenyl)-cyclohexyl-methanone: Add sodium azide (441 mg,6.785 mmol) to a stirred solution of 4-(cyclohexanecarbonyl)-benzylbromide (954 mg, 3.393 mmol) in anhydrous DMF (20 mL) and heat themixture to 90° C. for 2 h. Cool the mixture to room temperature, addwater and extract the aqueous solution with diethyl ether. Dry thecombined organic extracts over Na₂SO₄, filter and concentrate in vacuo.Purify the crude mixture by chromatography on silica gel eluting withhexane and hexane/EtOAc (19:1) to give the desired intermediate as oil(310 mg, 38%).N-(tert-Butoxycarbonyl)-4-cyclohexanecarbonyl-benzylamine: Add 10% Pd/C(100 mg) to a solution of (4-azidomethyl-phenyl)-cyclohexyl-methanone(310 mg, 1,274 mmol) and di-tert-butyl-dicarbonate (278 mg, 1274 mmol)in ethanol (5 mL). Submit the mixture to hydrogenation under atmosphericpressure (balloon) for 1 h. Filter the catalyst through Celite® andconcentrate the filtrate in vacuo. Purify the crude mixture bychromatography on silica gel eluting with hexane and hexane/EtOAc (92:8)to provide the desired intermediate as a white solid (197 mg, 49%).4-Cyclohexanecarbonyl-benzylamine: Add 4N hydrogen chloride in dioxane(1 mL) to a stirred solution ofN-(tert-butoxycarbonyl)-4-cyclohexanecarbonyl-benzylamine (197 mg, 0.621mmol) in anhydrous dichloromethane (4 mL) and stir the mixture atambient temperature for 16 h. Concentrate in vacuo and partition theresidue between dichloromethane and saturated aqueous NaHCO₃. Extractthe aqueous phase twice with dichloromethane. Dry the combined organicextracts over Na₂SO₄, filter and concentrate in vacuo to give the titlecompound (125 mg, 93%) that was used without any further purification.MS (ES+) m/z: 218 (M+H)⁺.

Preparation 268 4-(2-Cyclopentyl-acetyl)-benzylamine

2-Cyclopentyl-1-p-tolyl-ethanone: Add aluminum trichloride (2.719 g,20.4 mmol) in three portions to a solution of cyclopentylacetyl chloride(2 g, 13.6 mmol) in anhydrous toluene (30 mL) at 0° C. Stir the solutionat room temperature overnight. Cool to 0° C., add water and extract theaqueous phase with EtOAc. Dry the organic phase over MgSO₄, filter andconcentrate in vacuo. Purify the crude mixture by chromatography onsilica gel eluting with hexane and hexane/EtOAc (19:1) to give thedesired intermediate as an oil (2.5 g, 91%).1-(4-Bromomethyl-phenyl)-2-cyclopentyl-ethanone: Add NBS (523 mg, 2.94mmol) and AIBN (44 mg, 0.267 mmol) to a solution of2-cyclopentyl-1-p-tolyl-ethanone (540 mg, 2.67 mmol) in carbontetrachloride (80 mL) and heat overnight at 85° C. Add water and extractthe aqueous phase with dichloromethane. Dry the organic phase overMgSO₄, filter and concentrate in vacuo. Purify the crude mixture bychromatography on silica gel eluting with hexane and hexane/EtOAc (98:2,95:5) to obtain the desired intermediate as an oil (479 mg, 64%).N-Di-(tert-butoxycarbonyl)-4-(2-cyclopentyl-acetyl)-benzylamine: Addsodium hydride (42 mg, 1.65 mmol) to a solution ofdi-tert-butyl-iminodicarboxylate (262 mg, 1.21 mmol) in anhydrous DMF (5mL) at room temperature under nitrogen and stir for 5 min. Then add asolution of 1-(4-bromomethyl-phenyl)-2-cyclopentyl-ethanone (310 mg, 1.1mmol) in anhydrous DMF (15 mL) and stir for 1 h. Add water and extractthe aqueous phase twice with EtOAc. Wash the combined organic extractswith iced-water. Dry the organic layer over MgSO₄, filter andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (19:1) to obtain the desired intermediate (360 mg,78%).4-(2-Cyclopentyl-acetyl)-benzylamine: Add 4N hydrogen chloride indioxane (15 mL) to a solution ofN-di-(tert-butoxycarbonyl)-4-(2-cyclopentyl-acetyl)-benzylamine (300 mg,0.72 mmol) in EtOAc (20 mL) and stir overnight. Concentrate in vacuo,suspend the solid obtained in diethyl ether and add hexane. Filter andwash the solid with hexane. Suspend the solid into dichloromethane, addsaturated aqueous NaHCO₃ and stir until both phases are clear (15 min).Extract the aqueous phase with dichloromethane and EtOAc. Dry thecombined organic extracts over MgSO₄, filter and concentrate in vacuo toobtain the title compound as an oil that was used without any furtherpurification.

Preparation 268

The compound of Preparation 269 may be prepared essentially as describedin Preparation 268 by using cyclohexylacetyl chloride. Overall yield andMS (ES+) data are shown in the Table below.

Yield MS (ES+) Prep. NH—R Compound (%) m/z 269

4-(2-Cyclohexyl-acetyl)-benzylamine 40 232(M + H)⁺

Preparation 270 5-Aminomethyl-2-(3-methyl-butyryl)-pyridine

5-Azidomethyl-2-(3-methyl-butyryl)-pyridine: Add DBU (240 mg, 1.55 mmol)to a solution of 5-hydroxymethyl-2-(3-methyl-butyryl)-pyridine (250 mg,1.29 mmol) and diphenylphosphorylazide (430 mg, 1.55 mmol) in anhydroustoluene (10 mL) at 0° C. Stir at 0° C. for 30 min, warm to roomtemperature and stir for 4 h. Dilute with EtOAc and water. Extract theaqueous phase twice with EtOAc. Dry the combined organic extracts overNa₂SO₄, filter and concentrate in vacuo. Purify the crude mixture bychromatography on silica gel eluting with hexane and hexane/EtOAc (9:1)to provide the desired intermediate (300 mg, 99%). MS (ES+) m/z: 219(M+H)⁺.5-Aminomethyl-2-(1-hydroxy-3-methyl-butyl)-pyridine hydrochloride: Add10% Pd/C (20 mg) to a solution of5-azidomethyl-2-(3-methyl-butyryl)-pyridine (80 mg, 0.367 mmol) inethanol (10 mL) containing concentrated HCl (1 mL). Submit the mixtureto hydrogenation at atmospheric pressure for 2 h. Filter the reactionmixture over Celite® and concentrate in vacuo to afford the desiredintermediate (95 mg, 98%). MS (ES+) m/z: 195 (M+H)⁺.5-tert-Butoxycarbonylaminomethyl-2-(1-hydroxy-3-methyl-butyl)-pyridine:Add di-tert-butyl-dicarbonate (78 mg, 0.356 mmol) and triethylamine(0.149 mL, 1.068 mmol) to a solution of5-aminomethyl-2-(1-hydroxy-3-methyl-butyl)-pyridine hydrochloride (95mg, 0.356 mmol) in anhydrous dichloromethane (5 mL). Stir the solutionat room temperature for 3 h. Dilute the reaction mixture withdichloromethane and wash with water. Extract the aqueous phase withdichloromethane. Dry the combined organic extracts over Na₂SO₄, filterand concentrate in vacuo. Purify the crude mixture by chromatography onsilica gel eluting with hexane/EtOAc (4:1) to afford the desiredintermediate (60 mg, 59%).5-tert-Butoxycarbonylaminomethyl-2-(3-methyl-butyryl)pyridine: Addmanganese dioxide (240 mg) to a solution of5-tert-butoxycarbonylaminomethyl-2-(1-hydroxy-3-methyl-butyl)-pyridine(60 mg, 0.2 mmol) in anhydrous 1,4-dioxane (1 mL) at room temperature.Heat the reaction mixture at 70° C. for 2 h. Filter the reaction mixtureover Celite® and concentrate in vacuo to afford the desired intermediate(60 mg, 99%).5-Aminomethyl-2-(3-methyl-butyryl)-pyridine: Add 4N hydrogen chloride indioxane (0.5 mL) to a solution of5-tert-butoxycarbonylaminomethyl-2-(3-methyl-butyryl)-pyridine (60 mg,0.2 mmol) in anhydrous dichloromethane (2 mL) and stir the solutionovernight. Concentrate in vacuo and partition the residue betweensaturated aqueous NaHCO₃ and dichloromethane. Extract the aqueous phasewith dichloromethane (2×15 mL) and EtOAc (2×15 mL). Dry the combinedorganic extracts over Na₂SO₄, filter and concentrate in vacuo to obtainthe title compound (37 mg, 95%) that was used without any furtherpurification.

Preparation 271 2-Bromo-5-tert-butoxycarbonylaminomethyl-pyridine

2-Bromo-pyridine-5-carbaldehyde oxime: Add hydroxylamine hydrochloride(1.494 g, 21.504 mmol) and a solution of NaHCO₃ (2.71 g, 32.256 mmol) inwater (15 mL) to a solution of 2-bromo-5-formyl-pyridine (2 g, 10.752mmol, prepared by following the procedure described in J. Org. Chem.2004, 69, 250-262) in absolute ethanol (100 mL). Stir the mixture atroom temperature for 2 h. Concentrate in vacuo and partition the residuebetween EtOAc and water. Extract the aqueous phase with EtOAc. Dry thecombined organic extracts over Na₂SO₄, filter and concentrate in vacuo.Purify the crude mixture by chromatography on silica gel eluting withhexane and hexane/EtOAc (9:1, 4:1) to afford the desired intermediate asa solid (1.362 g, 63%).5-Aminomethyl-2-bromo-pyridine: Add dropwise a solution of2-bromo-pyridine-5-carbaldehyde oxime (0.5 g, 2.487 mmol) in DME (10 mL)to a solution of titanium(IV) chloride (0.573 mL, 5.223 mmol) and sodiumborohydride (395 mg, 10.445 mmol) in DME (20 mL) at 0° C. Allow themixture to warm to room temperature and stir for 3 h. Add water andremove the solvent in vacuo. Basify the mixture to pH 12 with 1N aqueousNaOH and extract with dichloromethane. Dry the combined organic extractsover Na₂SO₄, filter and concentrate in vacuo to afford the desiredintermediate (340 mg, 73%) that was used without further purification.2-Bromo-5-tert-butoxycarbonylaminomethyl-pyridine: Adddi-tert-butyl-dicarbonate (397 mg, 1.818 mmol) and triethylamine (0.507mL, 3.636 mmol) to a solution of 5-aminomethyl-2-bromo-pyridine (340 mg,1.818 mmol) in anhydrous dichloromethane (15 mL). Stir the solutionovernight at room temperature. Dilute the reaction mixture withdichloromethane and wash with water. Extract the aqueous phase withdichloromethane. Dry the combined organic extracts over Na₂SO₄, filterand concentrate in vacuo. Purify the crude mixture by chromatography onsilica gel eluting with hexane and hexane/EtOAc (4:1) to afford thetitle compound as a solid (322 mg, 62%).

Preparation 272 5-Aminomethyl-2-(3,3-dimethyl-butyryl)-pyridine

5-tert-Butoxycarbonylaminomethyl-2-(1-hydroxy-3,3-dimethyl-butyl)-pyridine:Add slowly butyllithium (1.088 mL, 1.741 mmol, 1.6M solution in hexane)to a solution of 2-bromo-5-tert-butoxycarbonylaminomethyl-pyridine (200mg, 0.696 mmol) in anhydrous THF (10 mL) at −78° C. Stir the mixture atthis temperature for 35 min. Add 3,3-dimethylbutyraldehyde (0.219 mL,1.741 mmol) and stir the mixture at −78° C. for 3 h. Quench the reactionmixture at −78° C. with brine. Extract the aqueous phase with EtOAc(3×15 mL). Dry the combined organic extracts over Na₂SO₄, filter andconcentrate in vacuo. Purify The crude mixture by chromatography onsilica gel eluting with hexane and hexane/EtOAc (3:2) to afford thedesired intermediate as a colorless oil (118 mg, 55%). MS (ES+) m/z: 309(M+H)⁺.5-tert-Butoxycarbonylaminomethyl-2-(3,3-dimethyl-butyryl)-pyridine: Addmanganese dioxide (472 mg, 5.429 mmol) to a solution of5-tert-butoxycarbonylaminomethyl-2-(1-hydroxy-3,3-diethyl-butyl)-pyridine(118 mg, 0.383 mmol) in anhydrous 1,4-dioxane (5 mL) at roomtemperature. Heat the reaction mixture at 70° C. overnight. Filter thereaction mixture over Celite® and concentrate in vacuo to obtain thedesired intermediate (104 mg, 89%).5-Aminomethyl-2-(3,3-dimethyl-butyryl)-pyridine: Add 4N hydrogenchloride in dioxane (1 mL) to a solution of5-tert-butoxycarbonylaminomethyl-2-(3,3-dimethyl-butyryl)-pyridine (104mg, 0.339 mmol) in anhydrous dichloromethane (4 mL) and stir thesolution overnight. Concentrate in vacuo and partition the residuebetween saturated aqueous NaHCO₃ and dichloromethane. Extract theaqueous phase with dichloromethane (2×15 mL) and EtOAc (2×15 mL). Drythe combined organic extracts over Na₂SO₄, filter and concentrate invacuo to obtain the title compound as an oil (62 mg, 88%) that was usedwithout any further purification. MS (ES+) m/z: 207 (M+H)⁺.

Preparation 273 4-Aminomethyl-N-cycloheptyl-2-fluoro-benzamide

Methyl 4-bromo-2-fluoro-benzoate: Dissolve 4-bromo-2-fluoro-benzoic acid(15 g, 68.5 mmol) in methanol (70 mL). Add concentrated sulfuric acid(500 μl) to the solution and heat the mixture to reflux for 20 h under anitrogen atmosphere. Cool the mixture to room temperature andconcentrate in vacuo. Dissolve the residue in EtOAc (200 mL) and washsuccessively with saturated aqueous NaHCO₃ (50 mL) and water (2×50 mL).Dry the organic layer over Na₂SO₄, filter and concentrate in vacuo toobtain the desired intermediate (15.4 g, 96%). GC-MS m/z: 232 (M⁺).Methyl 4-cyano-2-fluoro-benzoate: Slurry methyl4-bromo-2-fluoro-benzoate (5 g, 21.5 mmol) and copper(I) cyanide (3.8 g,42.9 mmol) in anhydrous DME (90 mL). Heat the mixture to reflux for 20 hunder a nitrogen atmosphere. Cool the mixture to room temperature,dilute with hexane/EtOAc (1:1, 300 mL) and water (150 mL). Filter themixture through Celite® washing with hexane/EtOAc (1:1) to reduce theemulsion layer. Separate the organic layer and extract the aqueous layerwith hexane/EtOAc (1:1, 2×200 mL). Dry the combined organic extractsover Na₂SO₄, filter and concentrate in vacuo. Purify the crude mixtureby chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1gradient) to obtain the desired intermediate (2.9 g, 76%). GC-MS m/z:179 (M⁺).4-Cyano-2-fluoro-benzoic acid: Dissolve methyl 4-cyano-2-fluoro-benzoate(2.9 g, 16.2 mmol) in absolute ethanol (100 mL). Add potassium hydroxide(4.5 g, 80.2 mmol) and stir the milky white mixture for 1.5 h. Dilutethe mixture with water (125 mL) and wash with diethyl ether (50 mL).Collect the aqueous layer and concentrate in vacuo until solids start toappear in the flask, then adjust the mixture to pH 1 with concentratedHCl. Extract the aqueous mixture with diethyl ether (3×500 mL). Combinethe organic extracts and concentrate in vacuo to obtain the desiredintermediate as a white solid (2.2 g, 83%).4-Cyano-N-cycloheptyl-2-fluoro-benzamide: Dissolve4-cyano-2-fluoro-benzoic acid (1 g, 6.1 mm ol) in anhydrous toluene (25mL) and thionyl chloride (15 mL). Stir the mixture for 1 h at 90° C.under a nitrogen atmosphere (quench aliquots with methanol and assay byHPLC to determine if starting material has been consumed). Cool thereaction to room temperature and concentrate in vacuo to obtain the acidchloride as a yellow oil (1.25 g). Dissolve the acid chloride (1.25 g)in diethyl ether (75 mL), add triethylamine (0.85 mL, 6.1 mmol) andcycloheptylamine (0.78 mL, 6.1 mmol). Stir the mixture at roomtemperature for 16 h under a nitrogen atmosphere. Quench the reactionwith saturated aqueous Na₂CO₃ (20 mL). Extract the mixture with EtOAc(30 mL). Dry the organic layer over Na₂SO₄, filter and concentrate invacuo to obtain the desired intermediate (1.45 g, 91%). GC-MS m/z: 260(M⁺).4-Aminomethyl-N-cycloheptyl-2-fluoro-benzamide: Add4-cyano-N-cycloheptyl-2-fluoro-benzamide (1.4 g, 5.4 mmol), 10% Pd/C(Degussa type E101, 415 mg), ethanol (40 mL), water (15 mL) and aceticacid (1.8 mL) to a pressure vessel. Pressurize the vessel to 55 psi withhydrogen, and stir the mixture for 0.5 h (monitor the reaction by TLC).Filter the mixture through Celite® and wash the cake with warm ethanolfollowed by dichloromethane under a nitrogen atmosphere. Concentrate thefiltrate in vacuo to obtain the product as the acetic acid salt. Use SCXchromatography to obtain the title compound (1.36 g, 95%). GC-MS m/z:264 (M⁺).

Preparation 274 4-Aminomethyl-N-cycloheptyl-3-fluoro-benzamide

4-Cyano-N-cycloheptyl-3-fluoro-benzamide: Dissolve4-cyano-3-fluoro-benzoic acid (1 g, 6.1 mmol) in anhydrous toluene (20mL) and thionyl chloride (10 mL). Stir the mixture for 1.5 h at 90° C.under a nitrogen atmosphere (quench aliquots with methanol and assay byHPLC to determine if staring material has been consumed). Cool thereaction to room temperature and concentrate in vacuo to obtain the acidchloride as a yellow oil. Dissolve the yellow oil in diethyl ether (50mL), add triethylamine (0.86 mL, 6.1 mmol) and cycloheptylamine (0.79mL, 6.1 mmol). Stir the mixture at room temperature for 16 h under anitrogen atmosphere. Quench the reaction with saturated aqueous Na₂CO₃(20 mL). Extract the mixture with EtOAc (2×50 mL). Dry the combinedorganic extracts over Na₂SO₄, filter and concentrate in vacuo to obtainthe desired intermediate (1.24 g, 77%). MS (ES−) m/z: 259.2 (M−H)⁺.4-Aminomethyl-N-cycloheptyl-3-fluoro-benzamide: Add4-cyano-N-cycloheptyl-3-fluoro-benzamide (0.86 g, 3.3 mmol), 10% Pd/C(Degussa type E101, 250 mg), ethanol (25 mL), water (9 mL) and aceticacid (1 mL) to a pressure vessel under a nitrogen atmosphere. Pressurizethe vessel to 50 psi with hydrogen, and stir the mixture for 0.5 h.Filter the mixture through Celite® and wash the cake with warm ethanolfollowed by dichloromethane under a nitrogen atmosphere. Concentrate thefiltrate in vacuo to obtain the title compound as the acetic acid salt.Use SCX chromatography to obtain the title compound (805 mg, 92%). MS(ES+) m/z: 265.3 (M+H)⁺.

Preparation 275 4-Aminomethyl-2-chloro-N-cycloheptyl-benzamide

2-Chloro-4-cyano-N-cycloheptyl-benzamide: Dissolve2-chloro-4-cyano-benzoic acid (1.1 g, 6 mmol) in anhydrous toluene (20mL) and thionyl chloride (15 mL). Stir the mixture for 1 h at 90° C.under a nitrogen atmosphere (quench aliquots with methanol and assay byHPLC to determine if starting material has been consumed). Cool thereaction to room temperature and concentrate in vacuo to obtain the acidchloride as an oil. Dissolve the oil in diethyl ether (40 mL), addtriethylamine (0.84 mL, 6 mmol) and cycloheptylamine (0.77 mL, 6 mmol).Stir the mixture at room temperature for 1 h under a nitrogenatmosphere. Quench the reaction with saturated aqueous Na₂CO₃ (20 mL).Extract the mixture with EtOAc (100 mL). Dry the organic layer overNa₂SO₄, filter and concentrate in vacuo. Purify the crude mixture bychromatography on silica gel eluting with dichloromethane to obtain thedesired intermediate (1.1 g, 66%). MS (ES+) m/z: 277.2 (M+H)⁺.4-tert-Butoxycarbonylaminomethyl-2-chloro-N-cycloheptyl-benzamide:Dissolve 2-chloro-4-cyano-N-cycloheptyl-benzamide (460 mg, 1.7 mmol) inmethanol (15 mL). Cool the solution to 0° C. under a nitrogen atmosphereand add di-tert-butyl dicarbonate (726 mg, 3.3 mmol) and nickel(II)chloride hexahydrate (40 mg, 0.17 mmol). Add then sodium borohydride(360 mg, 9.5 mmol) portionwise over 30 min. Stir at 0° C. for 1 h thenconcentrate the mixture in vacuo. Dilute the residue with EtOAc (100mL), wash with saturated aqueous NaHCO₃ (40 mL). Extract the aqueouslayer with EtOAc (3×40 mL). Dry the combined organic extracts overNa₂SO₄, filter and concentrate in vacuo. Purify the crude mixture bychromatography on silica gel eluting with EtOAc to obtain the desiredintermediate (627 mg, 99%). MS (ES+) m/z: 381.3 (M+H)⁺.4-Aminomethyl-2-chloro-N-cycloheptyl-benzamide: Dissolve4-tert-butoxycarbonylaminomethyl-2-chloro-N-cycloheptyl-benzamide (624mg, 1.6 mmol) in dichloromethane (30 mL) then add trifluoroacetic acid(2 mL). Stir the solution at room temperature under a nitrogenatmosphere for 1 h. Concentrate the mixture in vacuo. Purify the crudemixture by SCX chromatography to obtain the desired intermediate (395mg, 85%). MS (ES+) m/z: 281.2 (M+H)⁺.

Preparation 276 4-Aminomethyl-N-cycloheptyl-2-methyl-benzamide

4-Cyano-N-cycloheptyl-2-methyl-benzamide: Add cycloheptylamine (0.83 mL,6.5 mmol), HOBT (838 mg, 6.2 mmol), EDC (1.2 g, 6.2 mmol) anddiisopropylethylamine (3.2 mL, 18.6 mmol) to a solution of4-cyano-2-methyl-benzoic acid (1 g, 6.2 mmol) in dichloromethane (20 mL)at room temperature under a nitrogen atmosphere. Stir the mixture for 16h at room temperature. Wash the mixture with water (20 mL), separate andconcentrate the organic layer in vacuo. Purify the crude mixture bychromatography on silica gel eluting with hexane/EtOAc (19:1 to 3:2gradient) to obtain the desired intermediate (830 mg, 52%). MS (ES+)m/z: 257.3 (M+H)⁺.4-Aminomethyl-N-cycloheptyl-2-methyl-benzamide: Add4-cyano-N-cycloheptyl-2-methyl-benzamide (0.82 g, 3.2 mmol), ethanol (23mL), water (8 mL) and acetic acid (1 mL) to a pressure vessel. Heatvessel to 50° C. to dissolve all solids. Add 10% Pd/C (Degussa typeE101, 250 mg) under a nitrogen atmosphere, then pressurize the vessel to55 psi with hydrogen at ambient temperature. Stir the mixture for 40min. Filter the mixture through Celite® and wash the cake with warmethanol (50 mL) followed by dichloromethane (100 mL) under a nitrogenatmosphere. Concentrate the filtrate in vacuo to obtain the titlecompound as the acetic acid salt. Use SCX chromatography to obtain thetitle compound (820 mg, 98%). MS (ES+) m/z: 261.3 (M+H)⁺.

Preparation 277(R)-4-Aminomethyl-2-fluoro-N-(2,2,2-trifluoro-1-methyl-ethyl)-benzamide

(R)-4-Cyano-2-fluoro-N-(2,2,2-trifluoro-1-methyl-ethyl)-benzamide: Add(R)-(2,2,2-trifluoro-1-methyl)-ethylamine (0.909 g, 6.08 mmol), HOBT(0.82 g, 6.1 mmol), diisopropylethylamine (2.1 mL, 12 mmol) and EDC(1.17 g, 6.08 mmol) to a mixture of 4-cyano-2-fluorobenzoic acid (1.004g, 6.08 mmol) in anhydrous THF (40 mL) at room temperature. Stirovernight and partition the mixture between EtOAc (250 mL) and saturatedaqueous NaHCO₃ (100 mL). Dry the organic extract over Na₂SO₄, filter andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith dichloromethane/hexane (1:1 to 1:0 gradient over 71 min; 50 mL/min)to afford the desired intermediate as a white solid (0.985 g, 62%).(R)-4-Aminomethyl-2-fluoro-N-(2,2,2-trifluoro-1-methyl-ethyl)-benzamide:Combine a solution of(R)-4-cyano-2-fluoro-N-(2,2,2-trifluoro-1-methyl-ethyl)-benzamide (0.904g, 3.475 mmol) in absolute ethanol (26 mL), water (9.7 mL) and glacialacetic acid (1.2 mL) with 10% Pd/C (Degussa type E101, 0.27 g, 0.13mmol) under nitrogen. Purge the mixture with nitrogen and then withhydrogen. Stir the slurry at room temperature under hydrogen at 55 psifor 30 min. Purge the reaction mixture with nitrogen and then filter theslurry over Celite®. Wash the filter cake with ethanol (100 mL) and THF(100 mL). Concentrate the filtrate and purify by SCX chromatographyeluting with dichloromethane/methanol (1:1) to remove impurities andthen with dichloromethane/2M ammonia in methanol (1:1) to elute product.Concentrate to afford the title compound as a colorless oil (0.86 g,94%).

Preparation 2783-tert-Butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Methyl 4-aminomethyl-2-fluoro-benzoate: Combine a solution of methyl4-cyano-2-fluoro-benzoate (1 g, 5.58 mmol) in absolute ethanol (42 mL)and acetic acid (1.9 mL) with a mixture of 10% Pd/C (Degussa type E101,0.17 g, 0.078 mmol) in water (15.6 mL) at room temperature undernitrogen. Purge with nitrogen and then with hydrogen at 55 psi and stirfor 1 h. Purge the reaction with nitrogen, filter through Celite® andwash the filter cake with ethanol (100 mL), THF (100 mL) and isopropanol(100 mL). Concentrate in vacuo and purify by SCX chromatography and thenchromatography on silica gel (40 g RediSep® column) eluting withdichloromethane/2M ammonia in methanol (99:1 to 9:1 gradient over 30min; 35 mL/min) to afford the desired intermediate as a white solid(0.602 g, 59%).7-Chloro-6-(3-fluoro-4-methoxycarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.24 g, 2.91 mmol) with methyl 4-aminomethyl-2-fluoro-benzoate (1.065g, 5.821 mmol) by using tris(dibenzylideneacetone)dipalladium(0) (0.533g, 0.582 mmol), BINAP (0.725 g, 1.16 mmol) and cesium carbonate (3.32 g,10.2 mmol) under nitrogen in anhydrous toluene (20 mL). Purify bychromatography on silica gel eluting with hexane/EtOAc (19:1 to 1:1gradient over 71 min; 50 mL/min) to afford the desired intermediate as ayellow oil (1.3 g, 100%).7-Chloro-6-(3-fluoro-4-methoxycarbonyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add 1M aqueous NaOH (2.8 mL, 2.8 mmol) to a solution of7-chloro-6-(3-fluoro-4-methoxycarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.31 g, 2.86 mmol) in 1,4-dioxane (13.3 mL) and water (2.6 mL) at 11°C. Allow mixture to warm to room temperature and stir for 1 h.Concentrate in vacuo and partition the residue between dichloromethane(250 mL) and saturated aqueous NaHCO₃ (100 mL). Dry the organic phaseover Na₂SO₄, filter and concentrate in vacuo to afford the desiredintermediate that was used without further purification.3-tert-Butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add 1M aqueous NaOH (5.7 mL, 5.7 mmol) to a mixture of7-chloro-6-(3-fluoro-4-methoxycarbonyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.04 g, 2.86 mmol) in 1,4-dioxane (13.3 mL) and water (2.6 mL) at roomtemperature. Heat the mixture at 50° C. for 2 h. Cool the mixture to 0°C., add a solution of di-tert-butyl-dicarbonate (0.62 g, 2.9 mmol) in1,4-dioxane (2 mL) and stir at 0° C. for 2 h. Concentrate in vacuo, addEtOAc (50 mL), 1N aqueous KHSO₄ (5.7 mL, 5.7 mmol) and water (20 mL) topH=1. Dry the organic phase over Na₂SO₄, filter and concentrate in vacuoto afford the title compound as a yellow oil (1.25 g, 98%) that was usedwithout further purification. MS (ES+) m/z: 449.1 (M+H)⁺.

Preparation 279 5-Aminomethyl-2-cyclohexylamino-pyridine

6-Cyclohexylamino-nicotinonitrile: Add cyclohexylamine (7.1 g, 72 mmol)to a mixture of 6-chloronicotinitrile (1 g, 7.2 mmol), potassiumcarbonate (3 g, 21.7 mmol), and anhydrous DMF (10 mL). Heat the mixturein a sealed flask at 120° C. for 1.5 h. Cool the reaction to ambienttemperature, dilute with hexane/EtOAc (1:1, 100 mL) and wash the mixturewith aqueous 5% sodium chloride (3×30 mL). Collect the organic layer andconcentrate in vacuo to obtain the desired intermediate (1.4 g, 97%).GC-MS m/z: 201 (M⁺).5-Aminomethyl-2-cyclohexylamino-pyridine: Charge a solution of6-cyclohexylamino-nicotinonitrile (1.4 g, 7.1 mmol) in methanol (70 mL)and trifluoroacetic acid (5 mL) to a pressure vessel containing 10% Pd/C(Degussa type E101, 600 mg). Pressurize the vessel to 40 psi withhydrogen and stir for 2 h. Filter the mixture through Celite®, wash withwarm ethanol, and dichloromethane. Concentrate the filtrate in vacuo.Purify the crude mixture by chromatography on silica gel eluting withdichloromethane/2M ammonia in methanol (99:1 to 90:10 gradient) toobtain the title compound (920 mg, 54%). MS (ES+) m/z: 206.1 (M+H)⁺.

Preparation 280

The compound of Preparation 280 may be prepared essentially as describedin Preparation 279 using 6-chloronicotinonitrile andcylclohexylmethylamine. Overall yield and MS (ES+) data are shown in theTable below.

Yield MS (ES+) Prep. Structure Compound (%) m/z 280

5-Aminomethyl-2-cyclohexyl-methylamino-pyridine 95 220.3(M + H)⁺

Preparation 281 6-Benzylamino-pyridin-3-ylmethylamine

6-Benzylamino-nicotinonitrile: Heat 6-chloroniconitrile (0.58 g, 4.2mmol) and benzylamine (4.6 mL, 42 mmol) in anhydrous DMF (3 mL) at 120°C. for 4.5 h. Cool at room temperature. Dilute with water and extractwith EtOAc. Wash the organic phase with brine, dry over MgSO₄, filter,and concentrate in vacuo. Purify by chromatography on silica gel elutingsequentially with hexane/EtOAc (4:1, 2:1, 1:2) to give the desiredintermediate as a white solid (840 mg, 96%). MS (ES+) m/z: 210 (4+H)⁺.6-Benzylamino-pyridin-3-ylmethylamine: Stir6-benzylamino-nicotinonitrile (680 mg, 3.3 mmol) and 10% Pd/C (Degussatype E101) vigorously in absolute ethanol (80 mL) under hydrogen at 25psi for 1 h. Filter the solution through Celite® and concentrate invacuo. Purify by chromatography on silica gel eluting sequentially with2M ammonia in methanol/dichloromethane (4:96, 9:91) to give the titlecompound as a white solid (320 mg, 45%). MS (ES+) m/z: 214 (M+H)⁺.

Preparation 282(±)-4-[1-(1,1,2,2,2-Pentafluoroethyl)-ethoxy]-benzylamine

(±)-4-[1-(1,1,2,2,2-Pentafluoroethyl)-ethoxy]-benzonitrile: Addpotassium carbonate (27.4 g, 198 mmol) to a mixture of4-fluorobenzonitrile (8 g, 66 mmol) and(±)-3,3,4,4,4-pentafluoro-2-butanol (17.2 g, 105 mmol) in anhydrous DMF(60 mL). Heat the mixture in a sealed flask for 4 h at 130° C. Cool thereaction to ambient temperature, dilute with hexane/EtOAc (1:1, 350 mL)and wash with aqueous 5% sodium chloride (3×100 mL). Collect the organiclayer, dry over Na₂SO₄, filter and concentrate in vacuo to obtain thedesired intermediate (17.1 g, 98%). GC-MS m/z: 432 (M⁺).(±)-4-[1-(1,1,2,2,2-Pentafluoroethyl)-ethoxy]-benzylamine: Add(±)-4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzonitrile (1 g, 3.8mmol) to a slurry of lithium aluminum hydride (400 mg, 10 mmol) indiethyl ether (30 mL) at 0° C. under a nitrogen atmosphere. Stir themixture at ambient temperature for 2 h, and then quench the reactionsequentially with water (1 mL) and 5N sodium hydroxide (1 mL). Filterthe slurry through Celite®, dry the filtrate over Na₂SO₄, filter andconcentrate in vacuo to obtain the title compound (990 mg, 98%). GC-MSm/z: 268 (M⁺).

Preparation 283 4-[1-(1,1,2,2,2-Pentafluoroethyl)-ethoxy]-benzylamineIsomer

4-[1-(1,1,2,2,2-Pentafluoroethyl)-ethoxy]-benzonitrile Isomer 2:Separate (±)-4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzonitrile bynormal phase chiral chromatography (Chiralcel OJ, 8×33 cm, elute withheptane/3A ethanol 97:3, flow rate 375 mL/min). Collect the 2^(nd)eluting isomer as the desired intermediate (11.3 g, 40% recovery, 98.6%ee (Chiralcel OJ, 4.6×250 mm, elute with heptane/3A ethanol 97:3, 1mL/min). GC-MS m/z: 265 (M⁺).4-[1-(1,1,2,2,2-Pentafluoroethyl)-ethoxy]-benzylamine Isomer 2: Reduce4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzonitrile isomer 2 (11.4 g,43 mmol) using General Procedure 6-4 to obtain the title compound (11.38g, 98%). GC-MS m/z: 268

Preparation 284 4-[1-(1,1,2,2,2-Pentafluoroethyl)-ethoxy]-benzylamineIsomer 1

4-[1-(1,1,2,2,2-Pentafluoroethyl)-ethoxy]-benzonitrile Isomer 1:Separate (±)-4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzonitrile bynormal phase chiral chromatography (Chiralcel OJ, 8×33 cm, elute withheptane/3A ethanol 97:3, flow rate 375 mL/min). Collect the 1^(st)eluting isomer as the desired intermediate (4.5 g, 33% recovery, 99.3%ee (Chiralcel OJ, 4.6×250 mm, elute with heptane/3A ethanol 97:3, 1mL/min). GC-MS m/z: 265 (M⁺).4-[1-(1,1,2,2,2-Pentafluoroethyl)-ethoxy]-benzylamine Isomer 1: Reduce4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzonitrile isomer 1 (4.5 g,17 mmol) using General Procedure 64 to obtain the title compound (4.3 g,94%). GC-MS m/z: 268 (M⁺).

Preparation 285(±)-2-Aminomethyl-5-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-pyridine

5-Chloro-pyridine-2-carbonitrile: Slurry 2,5-dichloropyridine (6 g, 40.5mmol), zinc cyanide (2.9 g, 24.7 mmol), zinc (dust) (116 mg, 1.8 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexwith dichloromethane (720 mg, 0.98 mmol) in anhydrous DMF (40 mL). Heatthe mixture to reflux under a nitrogen atmosphere for 4.5 h. Cool themixture to room temperature, dilute with EtOAc (300 mL), wash withaqueous 10% sodium chloride (3×75 mL). Collect organic layer, dry overNa₂SO₄, filter and concentrate in vacuo. Purify by chromatography onsilica gel eluting with hexane/EtOAc (9:1 to 1:1 gradient) to obtain thedesired intermediate (2.6 g, 46%). GC-MS m/z: 138 (M⁺).(±)-4-[1-(1,1,2,2,2-Pentafluoroethyl)-ethoxy]-pyridine-2-carbonitrile:Add (±)-3,3,4,4,4-pentafluoro-2-butanol (710 mg, 4.3 mmol) slowly to aslurry of sodium hydride (104 mg, 1.2 equiv, 60% mineral oil, washedwith hexane) in hexamethylphosphoramide (2 mL) under nitrogen at 0° C.Allow the slurry to warm to ambient temperature and stir for 5 min. Add5-chloro-pyridine-2-carbonitrile (300 mg, 2.2 mmol), then heat themixture in a sealed flask at 130° C. for 4 h (monitor reaction byGC/MS). Cool the reaction to room temperature, adjust the mixture to pH9 with saturated aqueous Na₂CO₃, then extract with diethyl ether (2×50mL). Dry the combined organic extracts over Na₂SO₄, filter andconcentrate in vacuo. Purify the crude mixture by chromatography onsilica gel eluting with hexane/EtOAc (19:1 to 7:3 gradient) to obtainthe desired intermediate (380 mg, 66%). GC-MS m/z: 266 (M⁺).(±)-2-Aminomethyl-5-[1-(1,2,2,2-pentafluoroethyl)-ethoxy]-pyridine: Add(±)-4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-pyridine-2-carbonitrile(280 mg, 1 mmol), 10% Pd/C (Degussa type E101, 100 mg), methanol (20 mL)and trifluoroacetic acid (3 mL) to a pressure vessel. Pressurize thevessel to 40 psi with hydrogen, and stir the mixture for 1 h (monitorthe reaction by TLC). Filter the mixture through Celite® and wash thecake with warm ethanol followed by dichloromethane under a nitrogenatmosphere. Concentrate the filtrate in vacuo to obtain the crudeproduct as a trifluoroacetic acid salt Prepare the free base using SCXchromatography, then purify by chromatography on silica gel eluting withdichloromethane/2M ammonia in methanol (20:1) to obtain the titlecompound (172 mg, 61%). GC-MS m/z: 270 (M⁺).

Preparation 286 4-(1-Methyl-cyclohexylmethoxy)-benzylamine hydrochloride

4-(1-Methyl-cyclohexylmethoxy)-benzamide: Add a drop of anhydrous DMF toa mixture of 4-(1-methyl-cyclohexylmethoxy)-benzoic acid (prepared byfollowing the procedure described in Chem. Pharm. Bull. 1982, 30,3601-3616) (1 g, 4.03 mmol) and thionyl chloride (3.5 mL) at roomtemperature. Stir the mixture for 1.5 h and then remove the excess ofthionyl chloride in vacuo. Take-up the crude acid chloride in anhydrousTHF (10 mL) and add the resulting solution to cold concentrated NH₄OH(50 mL). Stir for 2.5 h at room temperature and concentrate in vacuo.Collect the solid formed via filtration and dry in vacuo to obtain thedesired intermediate (0.94 g, 94%). MS (ES+) m/z: 248 (M+H)⁺.4-(1-Methyl-cyclohexylmethoxy)-benzylamine hydrochloride: Add a solutionof 4-(1-methyl-cyclohexylmethoxy)-benzamide (6.82 g, 27.6 mmol) inanhydrous THF (75 mL) dropwise over 45 min to a slurry of lithiumaluminium hydride (1.57 g, 41.3 mmol) in diethyl ether (100 mL) at roomtemperature. After the addition is completed, heat the mixture at refluxfor 5.5 h. Cool the reaction mixture with an ice bath and quenchsequentially with water (1.6 mL), 5N aqueous NaOH (1.6 mL) and water(4.8 mL). Stir the resulting suspension for 1 h and remove the solidsformed via filtration through Celite® eluting with THF. Dry the filtrateover Na₂SO₄ and treat the solution with an excess of hydrogen chloridein diethyl ether. Concentrate the mixture in vacuo to obtain the titlecompound (6.68 g, 90%). MS (ES+) m/z: 233 (M+H)⁺.

Preparation 287 4-Cyclopentyloxy-benzylamine

4-Cyclopentyloxy-benzonitrile: Suspend sodium hydride (336 mg, 2.8 mmol,60% suspension in mineral oil) in anhydrous 1,4-dioxane (10 mL) undernitrogen atmosphere. Add cyclopentanol (620 mg, 7.2 mmol) and stir theresulting solution for 30 min. Add the preformed solution (3.35 mL, 2.4mmol) to neat 4-fluorobenzonitrile (240 mg, 2 mmol) in a microwave tubeand heat the sealed mixture at 100° C. for 30 min. Cool to roomtemperature and concentrate in vacuo. Purify by chromatography on silicagel eluting with isohexane/EtOAc (95:5 to 1:1 gradient) to obtain thedesired intermediate (300 mg, 80%). GC-MS m/z: 187 (M⁺).4-Cyclopentyloxy-benzylamine: Add a solution of 1M BH₃-THF complex inTHF (4.8 mL, 4.8 mmol) to neat 4-cyclopentyloxy-benzonitrile (300 mg,1.6 mmol) and stir the mixture for 3 h at room temperature and then for3 h at reflux. Cool to room temperature, pour the reaction into 2Naqueous HCl (10 mL) and stir the mixture for 1 h at room temperaturethen concentrate in vacuo. Dissolve the crude mixture in methanol andfilter through SCX column eluting with methanol followed by 3M ammoniain methanol to obtain the title compound (223 mg, 73%).

Preparations 288-292

The compounds of Preparations 288-292 may be prepared essentially asdescribed in Preparation 287 using the appropriate alcohols. ForPreparations 288, 290 and 291, sodium bis(trimethylsilyl)amide (1.2equiv., 2M solution in THF) was used as base in the first step. Overallyields and MS (EI) data are shown in the Table below.

MS Yield (EI) Prep. Structure Compound (%) m/z 288

4-Cyclohexyloxy-benzylamine 52 205(M⁺) 289

4-(Tetrahydro-pyran-4-yloxy)-benzylamine 42 207(M⁺) 290

3-(4-Aminomethyl-phenoxy)-2,2-dimethyl-propan-1-ol 38 209(M⁺) 291

(±)-4-(3,3-Dimethyl-cyclohexyloxy)-benzylamine 37 233(M⁺) 292

3-Chloro-4-cyclopentyloxy-benzylamine 42 225(M⁺)

Preparation 293 5-Aminomethyl-2-(3,3-dimethyl-butoxy)-

6-(3,3-Dimethyl-butoxy)-nicotinonitrile: Add sodiumbis(trimethylsilyl)amide (3.95 mL, 7.9 mmol, 2M solution in THF) to asolution of 3,3-dimethyl-butan-1-ol (960 CL, 7.9 mmol) in anhydrous THF(10 mL). Stir for 30 min at room temperature and then add a solution of6-chloro-nicotinonitrile (1 g, 7.2 mmol) in anhydrous THF (5 mL). Stirat room temperature overnight and then quench the reaction mixture withsaturated aqueous NaHCO₃ (100 mL). Extract the aqueous layer withdichloromethane (3×100 mL) and wash the organic layer with brine (100mL). Dry the combined organic extracts over MgSO₄ and concentrate invacuo to give the desired intermediate as a yellow solid (1.4 g, 94%).GC-MS m/z: 204 (Me).5-Aminomethyl-2-(3,3-dimethyl-butoxy)-pyridine: Dissolve6-(3,3-dimethyl-butoxy)-nicotinonitrile (1.4 g, 6.86 mmol) in anhydrousTHF (10 mL) under nitrogen and add 1M BH₃-THF complex in THF (20.6 mL,20.6 mmol). Stir the mixture overnight under nitrogen and then pour thereaction carefully into 5N aqueous HCl (20 mL). Stir the resultingsuspension for 6 h at room temperature. Then basify by adding 2N aqueousNaOH (50 mL) and extract with dichloromethane (3×100 mL). Dry thecombined organic extracts over MgSO₄, filter and concentrate in vacuo.Take-up the resulting oil in methanol and filter it through an SCXcolumn eluting with methanol followed by 3M ammonia in methanol.Concentrate in vacuo to obtain the title compound (754 g, 50%). GC-MSm/z: 208 (M>).

Preparation 294 3,3-Dimethylbutanethiol

Into four separate microwave tubes add thiourea (630 mg, 8.3 mmol) to asolution of 1-chloro-3,3-dimethylbutane (0.5 g, 4.4 mmol) in ethanol (5mL) and heat in a sealed tube in a microwave reactor at 150 W at 100° C.for 4 h. Cool to room temperature then stand over three days. Combinethe reactions and concentrate in vacuo to afford a white solid. Add 2Maqueous NaOH (50 mL) and heat at reflux overnight Cool to roomtemperature then acidify to pH 2 with 5M aqueous HCl (20 mL). Extractinto diethyl ether (50 mL), wash with brine (30 mL) then dry over MgSO₄and concentrate in vacuo to give the title compound as a clear oil (2 g,100%).

Preparation 295 5-Aminomethyl-2-tert-butylthio-pyridine

6-(tert-Butylthio)nicotinonitrile: Add sodium ethoxide (12 mL of 21% w/vin ethanol, 36 mmol) to a solution of 2-methyl-2-propanethiol (4.06 mL,36 mmol) in anhydrous ethanol (90 mL) at 0° C. under nitrogenatmosphere. Stir the solution and allow it to warm to room temperatureover 30 min. Add 6-chloronicotinonitrile (5 g, 36 mmol) and then heatthe reaction to reflux overnight. Cool to room temperature, addsaturated aqueous NaHCO₃ and concentrate in vacuo. Extract into EtOAc ordichloromethane and wash with brine. Dry over MgSO₄ and concentrate invacuo to give the desired intermediate as orange crystals (6.31 g, 91%).MS (ES+) m/z: 193 (M+H)⁺.5-Aminomethyl-2-tert-butylthio-pyridine: Use a method similar to theGeneral Procedure 6-5 to react 6-(tert-butylthio)nicotinonitrile (4.4 g,22.7 mmol) in anhydrous THF (25 mL) with 1M BH₃-THF complex in THF (25mL, 25 mmol). Add 5M aqueous HCl (10 mL) cautiously and stir the mixtureovernight at room temperature. Extract into EtOAc, wash with brine, dryover MgSO₄ and concentrate in vacuo to give an orange solid. Dissolvethe crude mixture in methanol and filter through an SCX column elutingwith methanol followed by 3M ammonia in methanol to obtain the titlecompound (2.74 g, 61%). MS (ES+) m/z: 197 (M+H)⁺.

Preparations 296-303

The compounds of Preparations 296-303 may be prepared essentially asdescribed in Preparation 295 using the appropriate thiol and6-chloronicotinonitrile (Preparations 296-298) or the appropriate arylfluoride (Preparations 299-303). Overall yields and MS (ES+) data areshown in the Table below.

Yield MS (ES+) Prep. Structure Compound (%) m/z 296

5-Aminomethyl-2-(3,3-dimethyl-butylthio)-pyridine 5 225(M + H)⁺ 297

5-Aminomethyl-2-cyclohexylthio-pyridine 47 223(M + H)⁺ 298

5-Aminomethyl-2-cyclopentylthio-pyridine 63 209(M + H)⁺ 299

4-Cyclohexylthio-benzylamine 30 205(M + H − NH₃)⁺ 300

4-Cyclohexylmethylthio-benzylamine 30 219(M + H − NH₃)⁺ 301

4-tert-Butylthio-3-chloro-benzylamine 52 213(M + H − NH₃)⁺ 302

4-Cyclohexylmethylthio-3-chloro-benzylamine 31 253(M + H − NH₃)⁺ 303

4-Cyclopentylthio-benzylamine 61 208(M + H − NH₃)⁺

Preparation 304 5-Aminomethyl-2-ethoxy-pyridine

6-(Ethoxy)nicotinonitrile: Add sodium ethoxide (1.6 mL of 21% w/v inethanol, 4.8 mmol) to a solution of 6-chloronicotinonitrile (612 mg,4.41 mmol) in anhydrous ethanol (15 mL) and heat the reaction at refluxfor 3 h. Cool to room temperature and stir overnight under nitrogenatmosphere. Concentrate in vacuo and dissolve the residue intodichloromethane. Wash with saturated aqueous NaHCO₃, dry over MgSO₄ andconcentrate in vacuo to give the desired intermediate as an off-whitesolid (545 mg, 83%).5-Aminomethyl-2-ethoxy-pyridine: Add a solution of 1M BH₃-THF complex inTHF (7 mL, 7 mmol) to a solution of 6-(ethoxy)nicotinonitrile (911 mg,4.41 mmol) in anhydrous THF (7 mL) and stir the mixture overnight atreflux. Add a second aliquot of 1M BH₃-THF complex in THF (7 mL, 7 mmol)and stir the mixture overnight at reflux. Add 5N aqueous HCl (10 mL)cautiously and stir the mixture overnight at room temperature.Concentrate in vacuo then dissolve the crude mixture in methanol andfilter through an SCX column eluting with methanol followed by 3Mammonia in methanol to obtain the title compound (250 mg, 40%). MS (ES+)m/z: 153 (M+H)⁺.

Preparation 305 4-Ethoxy-3-chloro-benzylamine

The compound of Preparation 305 may be prepared essentially as describedin Preparation 304 using the appropriate aryl fluoride (38% yield, MS(ES+) m/z 169 (M+H—NH₃)⁺).

Preparation 306 4-(Tetrahydro-pyran-4-yloxymethyl)-

4-(tetrahydro-pyran-4-yloxymethyl)-benzonitrile: Add sodiumbis(trimethylsilyl)amide (2.8 mL, 5.61 mmol, 2M solution in THF) to asolution of tetrahydro-pyran-4-ol (572 mg, 5.61 mmol) in anhydrous THF(20 mL) and stir for 30 min. Add a solution of4-bromomethyl-benzonitrile (1 g, 5.1 mmol) in anhydrous THF (5 mL) andstir the resulting mixture overnight at room temperature. Concentrate invacuo and purify the crude mixture by chromatography on silica geleluting with cyclohexane/EtOAc (98:2 to 1:1 gradient) to obtain thedesired intermediate as a white solid (845 mg, 76%). GC-MS m/z: 217(M⁺);4-(Tetrahydro-pyran-4-yloxymethyl)-benzylamine: Use a method similar tothe General Procedure 6-5 to reduce4-(tetrahydro-pyran-4-yloxymethyl)-benzonitrile (845 mg, 4 mmol). Refluxovernight to obtain the title compound (812 mg, 91%). MS (ES+) m/z:222.2 (M+H)⁺.

Preparations 307-309

The compounds of Preparations 307-309 may be prepared essentially asdescribed in Preparation 306 using 4-bromomethyl-benzonitrile and theappropriate alcohol. Overall yields and MS (ES+) data are shown in theTable below.

Yield MS (ES+) Prep. Structure Compound (%) m/z 307

4-tert-Butoxymethyl-benzylamine 22 194(M + H)⁺ 308

4-Cyclo-pentyloxy-methyl-benzylamine 72 206(M + H)⁺ 309

4-Cyclo-hexyloxy-methyl-benzylamine 58 220(M + H)⁺

Preparation 310 4-(2,2-Dimethyl-propoxymethyl)-benzylamine

4-(2,2-Dimethyl-propoxymethyl)-benzonitrile: Add sodiumbis(trimethylsilyl)amide (3 mL, 6 mmol, 2M solution in THF) to asolution of 2,2-dimethyl-1-propanol (528 mg, 6 mmol) in anhydrous1,4-dioxane. Stir until the suspension becomes homogenous. Then add asolution of 4-cyanobenzyl bromide (980 mg, 5 mmol) in anhydrous1,4-dioxane (3 mL). Heat the mixture in a microwave oven at 100° C. for30 min. Cool to room temperature, add water (50 mL) and extract withEtOAc (3×50 mL). Dry the combined organic extracts over MgSO₄, andconcentrate in vacuo. Purify the crude mixture by chromatography onsilica gel eluting with isohexane/EtOAc (95:5 to 1:1 gradient) to obtainthe desired intermediate (811 mg, 80%).4-(2,2-Dimethyl-propoxymethyl)-benzylamine: Add 1M BH₃-THF complex inTHF (16 mL, 16 mmol) to neat 4-(2,2-dimethyl-propoxymethyl)-benzonitrile(3.043 g, 15 mmol) and stir the mixture overnight at room temperature.Add methanol and stir until hydrogen evolution stops. Concentrate thesolution in vacuo. Dissolve the crude mixture in methanol and filterthrough an SCX column eluting with methanol followed by 3M ammonia inmethanol. Concentrate in vacuo to obtain the title compound (3 g, 96%).

Preparation 311 4-Cycloheptyloxy-benzylamine

4-Cycloheptyloxy-benzonitrile: Under a nitrogen atmosphere, add4-hydroxybenzonitrile (4 g, 33.5 mmol), cycloheptanol (2.55 g, 22.3mmol), tri-n-butylphosphine (8.25 mL, 33.5 mmol), and azodicarboxylatedipiperidine (8.45 g, 33.5 mmol) to anhydrous THF (60 mL) at 0° C. Stirthe mixture at 0° C. for 1 h and then at room temperature for 12 h.Dilute with EtOAc (50 mL) and water (50 mL). Separate the layers andextract the aqueous phase with EtOAc (4×30 mL). Wash the combinedorganic extracts with water (30 mL) and brine (20 mL). Dry over Na₂SO₄,filter and concentrate in vacuo. Purify the crude mixture bychromatography on silica gel (120 g RediSep column) eluting withhexane/EtOAc (1:0 to 1:1 gradient over 1.25 h; 80 mL/min) to provide thedesired intermediate as a colorless oil (2.77 g, 58%). MS (APCI) m/z:216 (M+H)⁺.4-Cycloheptyloxy-benzylamine: Dissolve 4-cycloheptyloxy-benzonitrile (2g, 9.29 mmol) in anhydrous THF (20 mL) and cool to 0° C. Add boranedimethylsulfide complex (2.8 mL, 27.9 mmol, 10-12 M solution), stir at0° C. for 0.5 h and then heat at reflux for 1 h. Cool the mixture to 0°C., add methanol (5 mL) and stir for 15 min. Add 2M aqueous HCl (15 mL)and stir for 30 min at room temperature. Concentrate the mixture invacuo and purify the residue by chromatography on silica gel (45 gRediSep column) eluting with a gradient of dichloromethane inchloroform/methanol/concentrated ammonium hydroxide (80:18:2) over 30min (80 ml/min) to provide the title compound as a colorless oil (1.87g, 97%). MS (APCI) m/z: 220 (M+H)⁺.

Preparation 312 4-Cycloheptylthio-benzylamine

Methyl 4-cycloheptylthio-benzoate: Under a nitrogen atmosphere, addmethyl 4-mercaptobenzoate (2.5 g, 15 mmol), cycloheptanol (2.55 g, 22.3mmol), tri-n-butylphosphine (5.26 g, 26 mmol) and azodicarboxylatedipiperidine (6.56 g, 26 mmol) to anhydrous THF (50 mL) at O—C. Stir themixture at 0° C. for 1 h and then at room temperature for 12 h. Dilutewith EtOAc (50 mL) and water (50 mL) and extract the aqueous phase withEtOAc (4×30 mL). Wash the combined organic extracts with water (30 mL)and brine (20 mL). Dry the organic phase over Na₂SO₄, filter andconcentrate in vacuo. Purify the crude mixture by chromatography onsilica gel (120 g RediSep column) eluting with hexane/EtOAc (1:0 to 1:1gradient over 1.25 h; 80 mL/min) to provide the desired intermediate asa colorless oil (1.12 g, 40%). MS (APCI) m/z: 265 (M+H)⁺.4-Cycloheptylthio-benzoic acid: Add methyl 4-cycloheptylthio-benzoate(1.1 g, 4.16 mmol) and sodium hydroxide (500 mg, 12.5 mmol) to methanol(20 mL) and stir overnight. Add 2M aqueous HCl (20 mL) and extract theaqueous phase with dichloromethane. Wash the combined organic extractswith water (20 mL) and brine (20 mL). Dry the organic solution overNa₂SO₄, filter and concentrate in vacuo to provide the desiredintermediate as a white solid (984 mg, 94%). MS (APCI) m/z: 251 (M+H)⁺.4-Cycloheptylthio-benzamide: Add thionyl chloride (1.35 mL, 18.4 mmol)to a mixture of 4-cycloheptylthio-benzoic acid (984 mg, 3.93 mmol) indichloromethane (15 mL) at 0° C. Heat the mixture to reflux for 1 h.Cool the mixture to room temperature and concentrate in vacuo. Dissolvethe residue in dichloromethane (20 mL) and cool to 0° C. Addtriethylamine (1.1 mL, 7.86 mmol) and bubble ammonia gas through thesolution Warm the mixture to room temperature and stir for 1 h. Dilutewith water (20 mL) and extract the aqueous phase with dichloromethane(3×20 mL). Wash the combined organic extracts with saturated aqueousNaHCO₃ (20 mL). Dry the organic solution over Na₂SO₄, filter andconcentrate in vacuo to provide the desired intermediate as an off-whitesolid (976 mg, 99%). MS (APCI) m/z: 250 (M+H)⁺.4-Cycloheptylthio-benzylamine: Under a nitrogen atmosphere, add4-cycloheptylthio-benzamide (976 mg, 3.91 mmol) to a slurry of lithiumaluminum hydride (0.398 mg, 11.7 mmol) in anhydrous THF (25 mL) at 0° C.Heat the mixture for 1 h. Cool the mixture to 0° C. and add diethylether (50 mL). Carefully add water (0.4 mL), 3M aqueous NaOH (0.4 mL)and water (1.2 mL). Filter the solid residue and concentrate thefiltrate in vacuo. Purify the crude mixture by chromatography on silicagel (45 g RediSep column) eluting with a gradient of dichloromethane inchloroform/methanol/concentrated ammonium hydroxide (80:18:2) over 45min (80 mL/min) to give the title compound as a colorless oil (530 mg,57%). MS (ES+) m/z: 236 (M+H)⁺.

Preparation 313 4-Cyclohexylmethyl-benzylamine hydrochloride

4-(Cyclohexyl-hydroxy-methyl)-benzonitrile: Dissolve4-formyl-benzonitrile (5 g, 38.1 mmol) in anhydrous toluene (50 mL). Addchlorodicyclohexylborane (39 mL, 39 mmol, 1M solution in hexane) and2,6-lutidine (4.25 mL, 39 mmol) and stir the mixture overnight at roomtemperature. Cool to 0° C., add aqueous hydrogen peroxide (5.4 mL, 48mmol, 30%) and 3M aqueous NaOH (16 mL, 48 mmol) and stir for 15 min. AddEtOAc and extract the aqueous phase with EtOAc. Wash the combinedorganic extracts with water and brine. Dry the organic solution overNa₂SO₄, filter and concentrate in vacuo. Purify the crude mixture bychromatography on silica gel (45 g RediSep column) eluting withhexane/EtOAc (1:0 to 1:1 gradient over 60 min; 80 mL/min) to provide thedesired intermediate as a clear oil (2.3 g, 23%). MS (APCI) z/z: 197(M-H₂O)⁺.4-(Cyclohexyl-methanesulfonyloxy-methyl)-benzonitrile: Dissolve4-(cyclohexyl-hydroxy-methyl)-benzonitrile (1 g, 4.66 mmol), andtriethylamine (1.3 mL, 9.3 mmol) in dichloromethane (20 mL). Cool themixture to 0° C., add methanesulfonyl chloride (1.49 mL, 5.34 mmol) andstir the solution for 2 h at 0° C. Add water (10 mL) and saturatedaqueous NaHCO₃ (10 mL). Separate the layers and extract back the aqueousphase with dichloromethane (3×20 mL). Combine the organic layers, washwith water (20 mL), dry over Na₂SO₄, filter and concentrate in vacuo toprovide the desired intermediate as a yellow oil (1.29 g, 94%). MS(APCI) m/z: 294 (M+H)⁺.4-Cyclohexylmethyl-benzylamine hydrochloride: Dissolve4-(cyclohexyl-methanesulfonyloxy-methyl)-benzonitrile (1.36 g, 4.64mmol) in diethyl ether (20 mL) and cool the solution to 0° C. Addlithium aluminum hydride (528 mg, 13.9 mmol) and stir the mixture at 0°C. for 2 h and then at room temperature for 3 h. Cool the mixture to 0°C. and carefully add water (0.5 mL), 3M aqueous NaOH (0.55 mL), andwater (1.5 mL). Filter the solid residue and concentrate the filtrate invacuo. Dissolve the crude mixture in diethyl ether and bubble hydrogenchloride to form a white precipitate. Filter and dry the solid in vacuoto provide the title compound as a white solid (420 mg, 44%). MS (APCI)m/z: 204 (M+H)⁺.

Preparation 314 4-(2-Methyl-butyl)-benzylamine

4-(1-Hydroxy-2-methyl-butyl)-1-bromo-benzene: Add slowly a solution of2-bromo-butane (4.8 g, 35 mmol) in anhydrous THF (20 mL) to a stirringmixture of magnesium (980 mg, 37 mmol) and anhydrous THF (10 mL) under anitrogen atmosphere. Heat the mixture at reflux for 30 min. Cool themixture to room temperature and add 4-bromo-benzaldehyde (5.36 g, 29mmol). After stirring for 5 min, cool the mixture in an ice-bath andacidify with 3N aqueous HCl (50 mL). Dilute the mixture with water andextract twice with diethyl ether. Wash the combined organic extractswith water and brine. Dry the organic phase over Na₂SO₄, filter andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (1:0, 20:1 and 1:1) to provide the desiredintermediate as a clear oil (2 g, 28%). MS (APCI) m/z: 243 (M+H)⁺.4-(1-Hydroxy-2-methyl-butyl)-benzonitrile: Add4-(1-hydroxy-2-methyl-butyl)-1-bromo-benzene (1.9 g, 7.8 mmol), zinccyanide (1.82 g, 15.6 mmol), and tetrakistriphenylphosphine palladium(0)(260 mg, 0.22 mmol) to anhydrous DMF (40 mL) under a nitrogenatmosphere. Heat the mixture at 90° C. for 12 h. Cool the mixture toroom temperature, dilute with water and extract the aqueous phase twicewith dichloromethane. Wash the combined organic extracts with water andbrine. Dry the organic solution over Na₂SO₄, filter and concentrate invacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc(1:0 and 20:1) to provide the desired intermediate (1.2 g, 75%). MS(APCI) m/z: 190 (M+H)⁺.4-(1-Methanesulfonyloxy-2-methyl-butyl)-benzonitrile: Addmethanesulfonyl chloride (540 mg, 4.72 mmol) to a solution of4-(1-hydroxy-2-methyl-butyl)-benzonitrile (800 mg, 4.23 mmol) andtriethylamine (0.88 mL, 6.35 mmol) in dichloromethane (10 mL) at 0° C.Warm the mixture to room temperature and stir for 1 h. Dilute themixture with water and dichloromethane. Extract the aqueous layer withdichloromethane. Wash the combined organic extracts with water. Dry theorganic solution over Na₂SO₄, filter and concentrate in vacuo to providethe desired intermediate as a clear oil (1.38 g) that was used withoutfurther purification. MS (APCI) m/z: 268 (M+H)⁺.4-(2-Methyl-butyl)-benzylamine: Under a nitrogen atmosphere, add amixture of 4-(1-methanesulfonyloxy-2-methyl-butyl)-benzonitrile (1.3 g,4.9 mmol) in diethyl ether (5 mL) to a slurry of lithium aluminumhydride (820 mg, 19.5 mmol) in diethyl ether (25 mL) at 0° C. Heat themixture under reflux for 1 h. Cool the mixture in an ice-bath and addwater (0.9 mL), 15% aqueous NaOH (0.9 mL) and water (2.8 mL). Apply themixture to a silica gel column eluting with dichloromethane and 5:1dichloromethane in chloroform/methanol/concentrated ammonium hydroxide(80:18:2) to provide the title compound (450 mg, 52%). MS (ES+) m/z: 178(M+H)⁺.

Preparation 315 4-(3,3-Dimethyl-butyl)-benzylamine

4-(3,3-Dimethyl-but-1-ynyl)-benzonitrile: Dissolve 4-bromobenzonitrile(3 g, 16.48 mmol) in anhydrous DMF (30 mL) in a sealed tube. Degas thesolution, purge with nitrogen and addtris(dibenzylideneacetone)dipalladium(0) (453 mg, 0.49 mmol), copper(I)iodide (188 mg, 0.99 mmol), triphenylphosphine (1.08 g, 4.12 mmol),triethylamine (10 mL) and 3,3-dimethylbutyne (6.1 mL, 49.44 mmol). Heatthe mixture at 90° C. overnight. Cool to room temperature, add water andextract the aqueous phase twice with EtOAc. Dry the combined organicextracts over MgSO₄, filter and concentrate in vacuo. Purify the crudemixture by chromatography on silica gel eluting with hexane andhexane/EtOAc (19:1, 9:1) to give the desired intermediate as a solid(2.75 g, 92%).N-(tert-Butoxycarbonyl)-4-(3,3-dimethyl-butyl)-benzylamine: Dissolve4-(3,3-dimethyl-but-1-ynyl)-benzonitrile (0.85 g, 4.64 mmol) in methanol(50 mL). Add 10% Pd/C (Degussa type E101, 0.68 g) anddi-tert-butyl-dicarbonate (1.21 g, 5.57 mmol). Submit the mixture tohydrogenation under atmospheric pressure (balloon) for 6 h. Filter thecatalyst through Celite® and concentrate the filtrate in vacuo. Purifythe crude mixture by chromatography on silica gel eluting with hexaneand hexane/EtOAc (9:1, 4:1) to provide the desired intermediate as anoil (1.25 g, 93%). MS (ES+) m/z: 314 (M+Na)⁺.4-(3,3-Dimethyl-butyl)-benzylamine: Add 4N hydrogen chloride in dioxane(15 mL) to a stirred solution ofN-(tert-butoxycarbonyl)-4-(3,3-dimethyl-butyl)-benzylamine (1.25 g, 4.29mmol) in methanol (20 mL) and stir at room overnight. Concentrate invacuo and wash the solid with diethyl ether. Suspend the solid indichloromethane and saturated aqueous NaHCO₃ and stir until both phasesare clear (15 min). Extract the aqueous phase twice withdichloromethane. Dry the combined organic extracts over MgSO₄, filterand concentrate in vacuo to give the title compound as an oil (0.654 g,80%) that was used without any further purification. MS (ES+) m/z: 192(M+H)⁺.

Preparation 316 3-Aminomethyl-6-(3,3-dimethyl-butyl)-pyridine

The title compound may be prepared essentially as described inPreparation 315 by using 6-bromonicotinonitrile (45% yield, MS (ES+) m/z193 (M+H)⁺).

Preparation 317 3-Aminomethyl-6-cyclohexylmethyl-pyridine

3-tert-Butoxycarbonylaminomethyl-cyclohexylmethyl-pyridine: Dissolve2-bromo-5-tert-butoxycarbonylaminomethyl-pyridine (500 mg, 1.74 mmol) inanhydrous THF (5 mL) in a sealed tube. Degas the solution, purge withnitrogen and add1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (127 mg,0.174 mmol) and 0.5M cyclohexylmethylzinc bromide in THF (10.4 mL, 5.22mmol). Heat the mixture at 60° C. overnight. Cool to room temperatureand dilute the reaction mixture with EtOAc. Add water and filter theprecipitate over Celite®. Dry the organic phase over MgSO₄, filter andconcentrate in vacuo. Purify the crude mixture by chromatography onsilica gel eluting with hexane and hexane/EtOAc (4:1, 3:2) to give thedesired intermediate as an oil (359 mg, 68%). MS (ES+) m/z: 305 (M+H)⁺.3-Aminomethyl-6-cyclohexylmethyl-pyridine: Add 4N hydrogen chloride indioxane (10 mL) to a solution of3-tert-butoxycarbonylaminomethyl-6-cyclohexylmethyl-pyridine (345 mg,1.13 mmol) in EtOAc (10 mL) and stir overnight Concentrate in vacuo,suspend the solid obtained in diethyl ether and add hexane. Filter andwash the solid with hexane. Suspend the solid into dichloromethane, addsaturated aqueous NaHCO₃ and stir until both phases are clear (15 min).Extract the aqueous phase twice with dichloromethane. Dry the combinedorganic extracts over MgSO₄, filter and concentrate in vacuo to obtainthe title compound as an oil (205 mg, 97%) that was used without anyfurther purification. MS (ES+) m/z: 205 (M+H)⁺.

Preparation 318 2-Aminomethyl-5-(3,3-dimethyl-butyl)-pyridine

5-(3,3-Dimethyl-but-1-ynyl)-2-cyano-pyridine: Dissolve5-bromo-2-cyano-pyridine (316 mg, 1.72 mmol) in anhydrous DMF (7 mL) ina sealed tube. Degas the solution, purge with nitrogen and addtris(dibenzylideneacetone)dipalladium(0) (47 mg, 0.05 mmol), copper(I)iodide (20 mg, 0.1 mmol), triphenylphosphine (113 mg, 0.43 mmol),triethylamine (2 mL) and 3,3-dimethylbutyne (0.64 mL, 5.16 mmol). Heatthe mixture at 90° C. overnight. Cool to room temperature, add water andextract the aqueous phase twice with EtOAc. Dry the combined organicextracts over MgSO₄, filter and concentrate in vacuo. Purify the crudemixture by chromatography on silica gel eluting with hexane andhexane/EtOAc (19:1) to give the desired intermediate as a solid (310 mg,97%).2-Aminomethyl-5-(3,3-dimethyl-butyl)-pyridine: Dissolve5-(3,3-dimethyl-but-1-ynyl)-2-cyano-pyridine (255 mg, 1.5 mmol) inmethanol (15 mL). Add 10% Pd/C (Degussa type E101, 230 mg) and submitthe mixture to hydrogenation under atmospheric pressure (balloon)overnight. Filter the catalyst through Celite® and concentrate thefiltrate in vacuo to provide the title compound as a solid (231 mg, 87%)that was used without any further purification. MS (ES+) m/z: 193(M+H)⁺.

Preparation 319 4-(1,3,3-Trimethyl-butyl)-benzylamine

4-(1-Hydroxy-1,3,3-trimethyl-butyl)-benzonitrile: Dissolve4-acetylbenzonitrile (1 g, 6.88 mmol) in diethyl ether/THF (1:1, 60 mL)and cool the solution to 0° C. Add 1M neopentylmagnesium chloride indiethyl ether (8.3 mL, 8.3 mmol) under nitrogen and stir the mixture atroom temperature overnight. Add saturated aqueous NH₄Cl and extract themixture twice with EtOAc. Dry the combined organic extracts over MgSO₄,filter and concentrate in vacuo. Purify the crude mixture bychromatography on silica gel eluting with hexane and hexane/EtOAc (19:1,9:1) to give the desired intermediate (364 mg, 24%).4-(3,3-Dimethyl-1-methylene-butyl)-benzonitrile: Add p-toluenesulfonicacid monohydrate (308 mg, 1-62 mmol) to a solution of4-(1-hydroxy-1,3,3-trimethyl-butyl)-benzonitrile (352 mg, 1.62 mmol) intoluene (10 mL). Heat the solution to 100° C. for 30 min. Cool thereaction mixture to room temperature, dilute the reaction mixture withEtOAc and wash the organic phase with saturated aqueous NaHCO₃. Dry theorganic phase over MgSO₄, filter and concentrate in vacuo. Purify thecrude mixture by chromatography on silica gel eluting with hexane andhexane/EtOAc (98:2, 19:1) to give the desired intermediate as an oil(200 mg, 62%).N-(tert-Butoxycarbonyl)-4-(1,3,3-trimethyl-butyl)-benzylamine: Dissolve4-(3,3-dimethyl-1-methylene-butyl)-benzonitrile (164 mg, 0.82 mmol) inmethanol (15 mL). Add 10% Pd/C (Degussa type E101, 130 mg) anddi-tert-butyl-dicarbonate (197 mg, 0.902 mmol). Submit the mixture tohydrogenation under atmospheric pressure (balloon) for 3 h. Filter thecatalyst through Celite® and concentrate the filtrate in vacuo. Purifythe crude mixture by chromatography on silica gel eluting with hexaneand hexane/EtOAc (19:1, 9:1) to provide the desired intermediate as anoil (227 mg, 90%). MS (ES+) m/z: 328 (M+Na)⁺.4-(1,3,3-Trimethyl-butyl)-benzylamine: Add 4N hydrogen chloride indioxane (10 mL) to a stirred solution ofN-(tert-butoxycarbonyl)-4-(1,3,3-trimethyl-butyl)-benzylamine (225 mg,0.74 mmol) in EtOAc (15 mL) and stir the mixture at ambient temperatureovernight. Concentrate in vacuo and wash the solid with diethyl ether.Suspend the solid in dichloromethane and saturated aqueous NaHCO₃ andstir until both phases are clear (15 min). Extract the aqueous phasetwice with dichloromethane. Dry the combined organic extracts overMgSO₄, filter and concentrate in vacuo to give the title compound as anoil (0.136 g, 90%) that was used without any further purification. MS(ES+) m/z: 206 (M+H)⁺.

EXAMPLE 5377-Chloro-6-(2,4-difluorobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1 to react7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(3 g, 7.06 mmol), palladium(II) acetate (0.16 g, 0.71 mmol), BINAP (0.88g, 1.41 mmol), 2,4-difluorobenzylamine (3.03 g, 21.18 mmol) and cesiumcarbonate (3.22 g, 9.88 mmol) in degassed toluene (120 mL). Degas themixture with vacuum/nitrogen purge and heat to 100° C. for 16 h. Coolthe mixture to room temperature, dilute with EtOAc, filter throughCelite® and concentrate in vacuo to give a brown oil. Purify the crudemixture by chromatography on silica gel eluting with hexane and thenhexane/THF (95:5) to obtain7-chloro-6-(2,4-difluorobenzylamino)-3-(2,2,2,trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas oil (2.25 g, 76%). MS (ES+) m/z: 419 (M+H)⁺.

Use a method similar to the General Procedure 1-2, using7-chloro-6-(2,4-difluorobenzylamino)-3-(2,2,2,trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(2.2 g, 5.26 mmol), to give the free base of the title compound as anoil (1.66 g, 98%) that solidified upon standing at room temperature andwas used without further purification. MS (ES+) m/z: 323 (M+H)⁺. Use amethod similar to the General Procedure 2-1, using7-chloro-6-(2,4-difluorobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.66 g, 5.14 mmol) to give the title compound as a white solid (2.03 g,90%). MS (ES+) m/z: 323 (M+H)⁺.

EXAMPLE 5387-Chloro-6-(2,5-difluorobenzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Example 538 may be prepared essentially as described in Example 537using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2,5-difluorobenzylamine (680% yield, MS (ES+) m/z 323 (M+H)⁺).

EXAMPLE 5397-Chloro-6-(2,2-difluoro-2-phenyl-ethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3 to react7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(541 mg, 1.274 mmol), palladium(II) acetate (57 mg, 0.225 mmol),tris(dibenzylideneacetone)dipalladium(0) (117 mg, 0.127 mmol), BINAP(0.506 g, 0.764 mmol), 2,2-difluoro-2-phenyl-ethylamine (400 mg, 2.547mmol) and cesium carbonate (830 mg, 2.548 mmol) in degassed toluene (35mL). Degas the mixture with vacuum/nitrogen purge and heat to 100° C.for 16 h. Cool the mixture to room temperature, dilute with EtOAc andfilter over Celite®. Purify the crude mixture by chromatography onsilica gel eluting with hexane and hexane/EtOAc (19:1) to obtain7-chloro-6-(2,2-difluoro-2-phenyl-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas oil (335 mg, 61%). MS (ES+) m/z: 433 (M+H)⁺.

Use a method similar to the General Procedure 1-2, using7-chloro-6-(2,2-difluoro-2-phenyl-ethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(317 mg, 0.734 mmol), to give the free base of the title compound as anoil (215 mg, 87%) that was used without further purification. MS (ES+)m/z: 337 (M+H)⁺. Use a method similar to the General Procedure 2-1,using7-chloro-6-(2,2-difluoro-2-phenyl-ethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(215 mg, 0.64 mmol) to give the title compound as a white solid (220 mg,76%). MS (ES+) m/z: 337 (M+H)⁺.

EXAMPLE 5407-Chloro-6-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Example 540 may be prepared essentially as described in Example 539using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2,2-difluoro-2-pyridin-2-yl-ethylamine (prepared by following theprocedure described in J. Med. Chem. 2003, 46, 461-473), (37% yield, MS(ES+) m/z 338 (M+H)⁺).

EXAMPLES 541-544

Examples 541-544 may be prepared essentially as described in Example 262by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

Yield MS (ES+) Ex. NH—R Compound (%) m/z 541

7-Chloro-6-(benzo[1,2,3]thiadiazol-6-yl-methylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride12 345(M + H)⁺ 542

7-Chloro-6-(2-cyclohexylmethyl-benzothiazol-6-yl-methylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 50 441(M + H)⁺ 543

7-Chloro-6-[(2-phenyl-benzothiazol-6-yl-methyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 27 420(M + H)⁺ 544

7-Chloro-6-(2-isobutyl-benzothiazol-5-yl-methylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 37 400(M + H)⁺

EXAMPLE 5457-Chloro-6-(3-phenyl-benzothiophen-6-yl-methylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine Hydrochloride

Use a method similar to the General Procedure 5-2, using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.28 g, 0.66 mmol) and 6-aminomethyl-3-phenyl-benzothiophene (0.19 g,0.8 mmol) with tris(dibenzylideneacetone)dipalladium(0) (120 mg, 0.13mmol), BINAP (165 mg, 0.26 mmol) and cesium carbonate (0.3 g, 0.93 mmol)at 90° C. for 17 h, to obtain7-chloro-6-(3-phenyl-benzothiophen-6-yl-methylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepinethat is used without further purification (234 mg, 69%). MS (ES+) m/z:515 (M+H)⁺.

Use a procedure similar to General Procedure 1-1 to deprotect7-chloro-6-(3-phenyl-benzothiophen-6-yl-methylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(234 mg, 0.45 mmol) in 7M ammonia in methanol (20 mL). Purify by reversephase HPLC (Vydac C18 5×25 cm, 30% to 100% acetonitrile in 0.1%TFA-water solution). Recover the free base by SCX chromatography andform the salt according to General Procedure 2-3 to obtain the titlecompound (38 mg, 17%). HRMS (ES+) m/z: 419.1340 (M+H)⁺.

EXAMPLE 5467-Chloro-6-[(difluoro-phenyl-methyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a procedure similar to Example 262 using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4-(difluoro-phenyl-methyl)-benzylamine, followed by deprotectionaccording to General Procedure 1-2 and salt formation according toGeneral Procedure 2-1 to obtain the title compound (175 mg, 77%). MS(ES+) m/z 413 (M+H)⁺.

EXAMPLE 5477-Chloro-6-[4-(3,3-dimethyl-butyryl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-3 to react7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(250 mg, 0.588 mmol), palladium(II) acetate (26 mg, 0.118 mmol),tris(dibenzylideneacetone)dipalladium(0) (53 mg, 0.059 mmol), BINAP(0.22 g, 0.353 mmol), 4-(3,3-dimethyl-butyryl)-benzylamine (241 mg,1.176 mmol) and cesium carbonate (383 mg, 1.176 mmol) in degassedtoluene (10 mL). Degas the mixture with vacuum/nitrogen purge and heatto 100° C. for 16 h. Cool the mixture to room temperature, dilute withEtOAc and wash with saturated aqueous NaHCO₃. Dry the organic layer overNa₂SO₄, filter and concentrate in vacuo. Purify the crude mixture bychromatography on silica gel eluting with hexane and then hexane/EtOAc(90:10, 85:15) to obtain7-chloro-6-[4-(3,3-dimethyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas oil (185 mg, 65%). MS (ES+) m/z: 481 (M+H)⁺.

Use a method similar to the General Procedure 1-2, using7-chloro-6-[4-(3,3-dimethyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(165 mg, 0.343 mmol), to give the free base of the title compound as anoil (130 mg, 98%) that was used without further purification. MS (ES+)m/z: 385 (M+H)⁺. Use a method similar to the General Procedure 2-1,using7-chloro-6-[4-(3,3-dimethyl-butyryl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(130 mg, 0.338 mmol) to give the title compound as a white solid (128mg, 76%). MS (ES+) m/z: 385 (M+H)⁺.

EXAMPLE 5487-Chloro-6-[4-(3,3-dimethyl-butyryl)-3-fluoro-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(96 mg, 0.225 mmol) with 4-(3,3-dimethyl-butyryl)-3-fluoro-benzylamine(105 mg, 0.45 mmol) by using tris(dibenzylideneacetone)dipalladium(0)(41 mg, 0.045 mmol), BINAP (56 mg, 0.09 mmol) and cesium carbonate (103mg, 0.315 mmol) in anhydrous toluene (15 mL). Purify by chromatographyon silica gel eluting with hexane/EtOAc (9:1) to give7-chloro-6-[4-(3,3-dimethyl-butyryl)-3-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (54 mg, 49%). MS (ES+) m/z: 499 (M+H)⁺.

Use a method similar to the General Procedure 1-2, using7-chloro-6-[4-(3,3-dimethyl-butyryl)-3-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(53 mg, 0.11 mmol) to give the free base of the title compound as ayellow oil (42 mg, 96%) that was used without further purification. Usea method similar to the General Procedure 2-1, using7-chloro-6-[4-(3,3-dimethyl-butyryl)-3-fluoro-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(42 mg, 0.105 mmol) to give the title compound as a white solid (30 mg,60%). MS (ES+) m/z: 403 (M+H)⁺.

EXAMPLE 5497-Chloro-6-[4-(3,3-dimethyl-butyryl)-2-fluoro-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(127 mg, 0.3 mmol) with 4-(3,3-dimethyl-butyryl)-2-fluoro-benzylamine(120 mg, 0.54 mmol) by using tris(dibenzylideneacetone)dipalladium(0)(27 mg, 0.03 mmol), BINAP (40 mg, 0.06 mmol) and cesium carbonate (137mg, 0.42 mmol) in anhydrous toluene (20 mL). Purify by chromatography onsilica gel eluting with hexane/EtOAc (19:1 and 9:1) followed by reversephase HPLC [Zorbax Bonus RP, 5 □M 21.2×100 mm, eluting withwater/acetonitrile (0.05% TFA in each) (35:65 to 15:85 gradient over 5min), flow rate 25 mL/min, UV detector (230 nm)] to give7-chloro-6-[4-(3,3-dimethyl-butyryl)-2-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (72 mg, 49%). MS (ES+) m/z: 499 (M+H)⁺.

Use a method similar to the General Procedure 1-2, using7-chloro-6-[4-(3,3-dimethyl-butyryl)-2-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(26 mg, 0.052 mmol) to give the free base of the title compound as ayellow oil (19 mg, 91%) that was used without further purification. Usea method similar to the General Procedure 2-1, using7-chloro-6-[4-(3,3-dimethyl-butyryl)-2-fluoro-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(18 mg, 0.045 mmol) to give the title compound as a white solid (20 mg,86%). MS (ES+) m/z: 403 (M+H)⁺.

EXAMPLE 5507-Chloro-6-[3-chloro-4-(3,3-dimethyl-butyryl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(90 mg, 0.212 mmol) with 3-chloro-4-(3,3-dimethyl-butyryl)-benzylamine(102 mg, 0.43 mmol) by using tris(dibenzylideneacetone)dipalladium(0)(39 mg, 0.0424 mmol), BINAP (53 mg, 0.0848 mmol) and cesium carbonate(97 mg, 0.297 mmol) in anhydrous toluene (10 mL). Purify bychromatography on silica gel eluting with hexane/EtOAc (9:1) to give7-chloro-6-[3-chloro-4-(3,3-dimethyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (72 mg, 49%). MS (ES+) m/z: 516 (M+H)⁺.

Use a method similar to the General Procedure 1-2, using7-chloro-6-[3-chloro-4-(3,3-dimethyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(70 mg, 0.136 mmol) to give the free base of the title compound as ayellow oil (57 mg, 99%) that was used without further purification. Usea method similar to the General Procedure 2-1, using7-chloro-6-[3-chloro-4-(3,3-dimethyl-butyryl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(57 mg, 0.136 mmol) to give the title compound as a white solid (50 mg,68%). MS (ES+) m/z: 420 (M+H)⁺.

EXAMPLE 5517-Chloro-6-[2-chloro-4-(3,3-dimethyl-butyryl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(300 mg, 0.71 mmol) with1-(4-aminomethyl-3-chloro-phenyl)-3,3-dimethyl-butan-1-one (338 mg, 1.41mmol) by using tris(dibenzylideneacetone)dipalladium(0) (130 mg, 9.142mmol), BINAP (177 mg, 0.284 mmol) and cesium carbonate (324 mg, 0.994mmol) in anhydrous toluene (31 mL). Purify by chromatography on silicagel eluting with hexane/EtOAc (92:8) followed by reverse phase HPLC[Hichrom Kromasil C18, 5 □M 21.2×100 mm, eluting with water/acetonitrile(0.05% TFA in each) (1:4 to 1:19 gradient over 5 min), flow rate 25mL/min, UV detector (230 nm)] to give7-chloro-6-[2-chloro-4-(3,3-dimethyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (77 mg, 21%). MS (ES+) m/z: 516 (M+H)⁺.

Use a method similar to the General Procedure 1-2, using7-chloro-6-[2-chloro-4-(3,3-dimethyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(77 mg, 0.15 mmol) to give the free base of the title compound as ayellow oil (93 mg, 99%) that was used without further purification. Usea method similar to the General Procedure 2-1, using7-chloro-6-[2-chloro-4-(3,3-dimethyl-butyryl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(63 mg, 0.15 mmol) to give the title compound as a white solid (52 mg,65%). MS (ES+) m/z: 420 (M+H)⁺.

EXAMPLE 5527-Chloro-6-[4-(4,4-dimethyl-pentanoyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to react7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(233 mg, 0.55 mmol), tris(dibenzylideneacetone)dipalladium(0) (50 mg,0.055 mmol), BINAP (73 mg, 0.11 mmol),4-[2-(3,3-dimethyl-butyl)-[1,3]dioxolan-2-yl]-benzylamine (263 mg, 1mmol) and cesium carbonate (250 mg, 0.77 mmol) in degassed toluene (20mL). Degas the mixture with vacuum/nitrogen purge and heat to 100° C.for 14 h. Cool the mixture to room temperature, dilute with EtOAc andfilter through Celite®. Purify the crude mixture by chromatography onsilica gel eluting with hexane and then hexane/EtOAc (19:1, 9:1 and 4:1)to obtain7-chloro-6-{4-[2-(3,3-dimethyl-butyl)-[1,3]dioxolan-2-yl]-benzylamine}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas oil (185 mg, 63%). MS (ES+) m/z: 539 (M+H)⁺.

Dissolve7-chloro-6-{4-[2-(3,3-dimethyl-butyl)-[1,3]dioxolan-2-yl]-benzylamine}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(185 mg, 0.34 mmol) in methanol (10 mL) and add 1N aqueous HCl (2 mL).Stir the mixture for 2 h and concentrate in vacuo. Dissolve the residuein dichloromethane and wash with saturated aqueous NaHCO₃. Dry theorganic phase over MgSO₄, filter and concentrate in vacuo to obtain7-chloro-6-[4-(4,4-dimethyl-pentanoyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (150 mg, 89%).

Use a method similar to the General Procedure 1-2, using7-chloro-6-[4-(4,4-dimethyl-pentanoyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(150 mg, 0.3 mmol), to give the free base of the title compound as anoil (100 mg, 83%) that was used without further purification. Use amethod similar to the General Procedure 2-1, using7-chloro-6-[4-(4,4-dimethyl-pentanoyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(100 mg, 0.25 mmol) to give the title compound as a solid (100 mg, 78%).MS (ES+) m/z: 399 (M+H)⁺.

EXAMPLE 5537-Chloro-6-(4-cyclohexanecarbonyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to react7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(150 mg, 0.353 mmol), tris(dibenzylideneacetone)dipalladium(0) (64 mg,0.071 mmol), BINAP (88 mg, 0.141 mmol),4-cyclohexanecarbonyl-benzylamine (125 mg, 0.576 mmol) and cesiumcarbonate (230 mg, 0.706 mmol) in degassed toluene (10 mL). Degas themixture with vacuum/nitrogen purge and heat to 100° C. for 6 h. Cool themixture to room temperature, dilute with EtOAc and filter throughCelite®. Purify the crude mixture by chromatography on silica geleluting with hexane and then hexane/EtOAc (90:10 and 85:15) to obtain7-chloro-6-(4-cyclohexanecarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas oil (130 mg, 75%). MS (ES+) m/z: 493 (M+H)⁺.

Use a method similar to the General Procedure 1-2, using7-chloro-6-(4-cyclohexanecarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(120 mg, 0.243 mmol), to give the free base of the title compound as anoil (86 mg, 89%) that was used without further purification. MS (ES+)m/z: 397 (M+H)⁺. Use a method similar to the General Procedure 2-1,using7-chloro-6-(4-cyclohexanecarbonyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(86 mg, 0.217 mmol) to give the title compound as a solid (85 mg, 77%).MS (ES+) m/z: 397 (M+H)⁺.

EXAMPLES 554-557

Examples 554-557 may be prepared essentially as described in Example 553using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

Yield MS (ES+) Ex. Structure Compound (%) m/z 554

7-Chloro-6-[4-(2-cyclopentyl-acetyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate64 397(M + H)⁺ 555

7-Chloro-6-[4-(2-cyclohexyl-acetyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate30 411(M + H)⁺ 556

7-Chloro-6-[6-(3-methyl-butyryl)-pyridin-3-yl-methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate35 372(M + H)⁺ 557

7-Chloro-6-[6-(3,3-dimethyl-butyryl)-pyridin-3-yl-methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate30 386(M + H)⁺

EXAMPLE 5587-Chloro-6-(4-cycloheptylcarbamoyl-3-fluoro-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.1 g, 2.5 mmol) with 4-aminomethyl-N-cycloheptyl-2-fluoro-benzamide(1.35 g, 5.1 mmol) in anhydrous toluene (25 mL). Purify bychromatography on silica gel eluting with hexane/EtOAc (19:1 to 1:1gradient) followed by SCX chromatography to obtain7-chloro-6-[4-cycloheptylcarbamoyl-3-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(720 mg, 53%). MS (ES+) m/z: 540.2 (M+H)⁺.

Use a method similar to the General Procedure 1-2 to deprotect7-chloro-6-[4-cycloheptylcarbamoyl-3-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by chromatography on silica gel eluting with dichloromethane/2Mammonia in methanol (99:1 to 90:10 gradient) to obtain the free base ofthe title compound. Use a method similar to the General Procedure 2-1 toobtain the title compound (665 mg, 89%). MS (ES+) m/z: 444.2 (M+H)⁺.

EXAMPLE 5597-Chloro-6-(4-cycloheptylcarbamoyl-2-fluoro-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(640 mg, 1.5 mmol) with 4-aminomethyl-N-cycloheptyl-3-fluoro-benzamide(795 mg, 3 mmol) in anhydrous toluene (20 mL). Purify the crude mixtureby chromatography on silica gel eluting with hexane/EtOAc (19:1 to 3:2gradient) to obtain7-chloro-6-(4-cycloheptylcarbamoyl-2-fluoro-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(568 mg, 70%). MS (ES+) m/z: 540.2 (M+H)⁺.

Use a method similar to the General Procedure 1-2 to deprotect7-chloro-6-(4-cycloheptylcarbamoyl-2-fluoro-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by chromatography on silica gel eluting with dichloromethane/2Mammonia in methanol (99/1 to 93/7 gradient) to give the free base of thetitle compound. Dissolve the free base (400 mg, 0.9 mmol) and L-tartaricacid (135 mg, 0.9 mmol) in methanol. Concentrate in vacuo to an oil.Triturate oil with dichloromethane and remove solvent in vacuo to obtainthe title compound as a solid (460 mg, 74%). MS (ES+) m/z: 444.2 (M+H)⁺.

EXAMPLE 5607-Chloro-6-(3-chloro-4-cycloheptylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate

Example 560 may be prepared essentially as described in Example 559 byusing7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4-aminomethyl-2-chloro-N-cycloheptyl-benzamide (50% yield, MS (ES+)m/z 460.2 (M+H)⁺).

EXAMPLE 5617-Chloro-6-(4-cycloheptylcarbamoyl-3-methyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(660 mg, 1.6 mmol) with 4-aminomethyl-N-cycloheptyl-2-methyl-benzamide(810 mg, 3.1 mmol) in anhydrous toluene (18 mL). Purify the crudemixture by chromatography on silica gel eluting with hexane/THF (19:1 to7:3 gradient) to obtain7-chloro-6-(4-cycloheptylcarbamoyl-3-methyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(690 mg, 83%). MS (ES+) m/z: 536.3 (M+H)⁺.

Use a method similar to the General Procedure 1-3 to deprotect7-chloro-6-(4-cycloheptylcarbamoyl-3-methyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(680 mg, 1.3 mmol). Purify by chromatography on silica gel eluting withdichloromethane/2M ammonia in methanol (99:1 to 97:3 gradient) to givethe free base of the title compound. Use a method similar to the GeneralProcedure 2-1 to obtain the title compound (473 mg, 65%). MS (ES+) m/z:440.3 (M+H)⁺.

EXAMPLE 562(R)-7-Chloro-6-[3-fluoro-4-(2,2,2-trifluoro-1-methyl-ethylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.561 g, 1.319 mmol) with(R)-4-aminomethyl-2-fluoro-N-(2,2,2-trifluoro-1-methyl-ethyl)-benzamide(0.698 g, 2.642 mmol) by using tris(dibenzylideneacetone)dipalladium(0)(0.241 g, 0.264 mmol), BINAP (0.33 g, 0.53 mmol) and cesium carbonate(1.51 g, 4.63 mmol) in anhydrous toluene (13 mL). Purify bychromatography on silica gel (40 g RediSep® column) eluting withhexane/EtOAc (19:1 to 1:1 gradient over 30 min; 35 mL/min) and then bySCX chromatography to afford(R)-7-chloro-6-[3-fluoro-4-(2,2,2-trifluoro-1-methyl-ethylcarbamoyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil (0.444 g, 62%). MS (ES+) m/z: 540.1 (M+H)⁺.

Use a method similar to the General Procedure 1-3 to deprotect(R)-7-chloro-6-[3-fluoro-4-(2,2,2-trifluoro-1-methyl-ethylcarbamoyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.224 g, 0.415 mmol). Purify by chromatography on silica gel (12 gRediSep® column) eluting with dichloromethane/2M ammonia in methanol(99:1 to 90:10 gradient over 30-min; 35 mL/min) to afford the free baseof the title compound as a white foam (0.142 g, 77%). Use a methodsimilar to the General Procedure 2-1, using(R)-7-chloro-6-[3-fluoro-4-(2,2,2-trifluoro-1-methyl-ethylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.132 g, 0.299 mmol) to afford the title compound as a white solid(0.135 g, 80%). MS (ES+) m/z: 444.2 (M+H)⁺.

EXAMPLE 5637-Chloro-6-(3-fluoro-4-isopropylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Add isopropylamine (0.15 mL, 1.8 mmol), HOBT (0.24 g, 1.8 mmol),diisopropylethylamine (0.63 mL, 3.6 mmol) and EDC (0.34 g, 1.8 mmol) toa mixture of3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.403 g, 0.9 mmol) in anhydrous THF (11.8 mL) at room temperature. Stirovernight at room temperature and partition the mixture between EtOAc(250 mL) and saturated aqueous NaHCO₃ (100 mL). Dry the organic phaseover Na₂SO₄, filter and concentrate in vacuo. Purify by chromatographyon silica gel (40 g RediSep® column) eluting with hexane/EtOAc (19:1 to1:1 gradient over 30 min; 50 mL/min) to afford3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-isopropylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a thick colorless oil (0.439 g, 100%). MS (ES+) m/z: 490.2 (M+H)⁺.

Use a method similar to the General Procedure 14 to deprotect3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-isopropylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.406 g, 0.83 mmol) in 1,4-dioxane (12.8 mL). Purify by SCXchromatography eluting with dichloromethane and dichloromethane/2Mammonia in methanol (1:1) followed by chromatography on silica gel (40 gRediSep column) eluting with dichloromethane/2M ammonia in methanol(99:1 to 90:10 over 30 min) and then dichloromethane/2M ammonia inmethanol (90:10 over 30 min; 35 mL/min) to afford7-chloro-6-(3-fluoro-4-isopropylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil (0.3237 g). MS (ES+) m/z: 390.1 (M+H)⁺. Use a methodsimilar to the General Procedure 2-1, using7-chloro-6-(3-fluoro-4-isopropylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.301 g, 0.772 mmol) to provide the title compound as a beige solid(0.328 g, 84%). MS (ES+) m/z: 390.1 (M+H)⁺.

EXAMPLE 5647-Chloro-6-(3-fluoro-4-propylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate

Add a solution of n-propylamine (6.3 mg, 0.11 mmol) in anhydrous THF(0.5 mL), HOBT (14.5 mg, 0.11 mmol), a solution of diisopropylamine(27.7 mg, 0.21 mmol) in anhydrous THF (0.5 mL) and EDC (20.5 mg, 6.11mmol) to a mixture of3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(48.1 mg, 0.11 mmol) in anhydrous THF (1.4 mL) at room temperature. Stirovernight at room temperature and partition the mixture between EtOAc(50 mL) and saturated aqueous NaHCO₃ (20 mL). Dry the organic phase overNa₂SO₄, filter and concentrate in vacuo. Purify by chromatography onsilica gel (12 g RediSep® column) eluting with hexane/EtOAc (19:1 to 1:1gradient over 30 min; 35 mL/min) to afford3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-propylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a thick colorless oil (37.1 mg, 71%). MS (ES+) m/z: 490.2 (M+H)⁺.

Use a method similar to the General Procedure 1-4 to deprotect3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-propylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(33.1 mg, 0.83 mmol) in 1,4-dioxane (1 mL). Purify by SCX chromatographyeluting with dichloromethane and dichloromethane/2M ammonia in methanol(1:1) to afford7-Chloro-6-(3-fluoro-4-propylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil (25.2 mg, 96%). MS (ES+) m/z: 390.1 (M+H)⁺. Use amethod similar to the General Procedure 2-6, using7-chloro-6-(3-fluoro-4-propylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(25 mg, 0.064 mmol) to provide the title compound as a white foam (31.4mg, 91%). MS (ES+) m/z: 390.1 (M+H)⁺.

EXAMPLE 5657-Chloro-6-[4-(cyclohexylmethylcarbamoyl)-3-fluoro-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate

Example 565 may be prepared essentially as described in Example 564 byusing3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand cyclohexylmethylamine (67% yield, MS (ES+) m/z 444 (M+H)⁺).

EXAMPLE 5667-Chloro-6-(6-cyclohexylamino-pyridin-3-ylmethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(800 mg, 1.9 mmol) with 5-aminomethyl-2-cyclohexylamino-pyridine (910mg, 4.4 mmol) in anhydrous toluene (15 mL). Purify the residue bychromatography on silica gel eluting with hexane/EtOAc (19:1 to 3:2gradient) to obtain7-chloro-6-(6-cyclohexylamino-pyridin-3-ylmethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(520 mg, 58%). MS (ES+) m/z: 481.0 (M+H)⁺.

Use a method similar to the General Procedure 1-3 to deprotect7-chloro-6-(6-cyclohexylamino-pyridin-3-ylmethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by chromatography on silica gel eluting with dichloromethane/2Mammonia in methanol (99/1 to 85/15 gradient) to give the free base ofthe title compound. Use a method similar to the General Procedure 2-1 toobtain the title compound (360 mg, 66%). MS (ES+) m/z: 385.1 (M+H)⁺.

EXAMPLE 5677-Chloro-6-(6-cyclohexylmethylamino-pyridin-3-ylmethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

The title compound may be prepared essentially as described in Example566 by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 5-aminomethyl-2-cyclohexylmethylamino-pyridine (22% yield, MS (ES+)m/z 399.1 (M+H)⁺).

EXAMPLE 5686-[6-(Benzylamino)-pyridin-3-ylmethylamino]-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to General Procedure 5-2 to couple6-benzylamino-pyridin-3-ylmethylamine and7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineto give, after deprotection and salt formation by methods similar to theGeneral Procedures 1-3 and 2-1, the title compound as an off-white solid(45% overall yield). HRMS (ES+) m/z: 393.1836 (M+H)⁺.

EXAMPLE 569(±)-7-Chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(751 mg, 1.8 mmol) with(±)-4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamine (950 mg, 3.5mmol) in anhydrous toluene (20 mL). Purify the crude mixture bychromatography on silica gel eluting sequentially with hexane/EtOAc(10:1, 5:1, 3:1) to obtain(±)-7-chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(990 mg, 99%).

Use a method similar to the General Procedure 1-3 to deprotect(±)-7-chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(980 mg, 1.8 mmol). Purify by chromatography on silica gel eluting withdichloromethane/2M ammonia in methanol (99:1 to 90:10 gradient) to givethe free base of the title compound. Use a method similar to the GeneralProcedure 2-1 to obtain the title compound (650 mg, 64%). MS (ES+) m/z:449.1 (M+H)⁺.

EXAMPLE 570(−)-7-Chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(9 g, 21.1 mmol) with4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamine isomer 2 (11.4 g,42.3 mmol) in anhydrous toluene (270 mL). Purify the crude mixture bychromatography on silica gel eluting with hexane/EtOAc (19:1 to 4:1gradient) to obtain7-chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineisomer 2 (9.5 g, 83%).

Use a method similar to the General Procedure 1-3 to deprotect7-chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineisomer 2 (9.5 g, 17.4 mmol). Purify by chromatography on silica geleluting with dichloromethane/2M ammonia in methanol (99:1 to 90:10gradient) to give the free base of the title compound. Use a methodsimilar to the General Procedure 2-1 to obtain the title compound (5.9g, 60%). MS (ES+) m/z: 449.1 (M+H)⁺. [α]²⁰ _(D) −11.6° (c 0.5, MeOH).

EXAMPLE 571(+)-7-Chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(3.4 g, 8 mmol) with4-[1-(1,1,2,2,2-pentafluoroethyl)ethoxy]-benzylamine isomer 1 (4.3 g, 16mmol) in anhydrous toluene (100 mL). Purify the crude mixture bychromatography on silica gel eluting with hexane/EtOAc (19:1 to 3:1gradient) to obtain7-chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepineisomer 1 (3.7 g, 85%).

Use a method similar to the General Procedure 1-3 to deprotect7-chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineisomer 1 (3.7 g, 6.8 mmol). Purify by chromatography on silica geleluting with dichloromethane/2M ammonia in methanol (99:1 to 97:3gradient) to give the free base of the title compound. Use a methodsimilar to the General Procedure 2-1 to obtain the title compound (2.8g, 74%). MS (ES+) m/z: 449.1 (M+H)⁺. [α]²⁰ _(D) +13.0° (c 0.5, MeOH).

EXAMPLE 572(±)-7-Chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-pyridin-2-ylmethylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(268 mg, 0.6 mmol) with(±)-2-aminomethyl-5-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-pyridine(170 mg, 0.6 mmol) in anhydrous toluene (3 mL). Purify the crude mixtureby chromatography on silica gel eluting sequentially with hexane/EtOAc(10:1, 5:1, 3:1) to obtain(±)-7-chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-pyridin-2-ylmethylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(270 mg, 79%). MS (ES+) m/z: 546.1 (M+H)⁺.

Use a method similar to the General Procedure 1-3 to deprotect(±)-7-chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-pyridin-2-ylmethylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(265 mg, 0.5 mmol). Purify by chromatography on silica gel eluting withdichloromethane/2M ammonia in methanol (99:1 to 90:10 gradient) to givethe free base of the title compound. Use a method similar to the GeneralProcedure 2-1 to obtain the title compound (172 mg, 63%). MS (ES+) m/z:450.1 (M+H)⁺.

EXAMPLE 573(−)-7-Chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-pyridin-2-ylmethylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Separate(±)-7-chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-pyridin-2-ylmethylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate (172 mg) by normal phase chiral chromatography (Chiralcel OD,8×35 cm, eluting with heptane/isopropanol 4:1 with 0.2% DMEA). Collectthe 1^(st) eluting isomer, then use a method similar to the GeneralProcedure 2-1 to obtain the title compound [50 mg, 96.3% ee (ChiralcelOD-H, 4.6×150 mm, eluting with heptane/isopropanol 4:1 with 0.2% DMEA,0.6 mL/min)]. MS (ES+) m/z: 450.1 (M+H)⁺. [α]²⁰ _(D) −10.5° (c 0.5,MeOH).

EXAMPLE 574(+)-7-Chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-pyridin-2-ylmethylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Separate(4)-7-chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-pyridin-2-ylmethylamino}-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate (172 mg) by normal phase chiral chromatography (Chiralcel OD,8×35 cm, eluting with heptane/isopropanol 4:1 with 0.2% DMEA). Collectthe 2^(nd) eluting isomer, then use a method similar to the GeneralProcedure 2-1 to obtain the title compound [41 mg, 95.6% ee (ChirialcelOD-H, 4.6×150 mm, eluting with heptane/isopropanol 4:1 with 0.2% DMEA,0.6 mL/min)]. MS (ES+) m/z: 450.1 (M+H)⁺. [α]²⁰ _(D) +13.1° (c 0.5,MeOH).

EXAMPLE 5757-Chloro-6-[4-(1-methyl-cyclohexylmethoxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.47 mmol) with 4-(1-methyl-cyclohexylmethoxy)-benzylamine (120mg, 0.51 mmol) in anhydrous 1,4-dioxane (7 mL). Purify the crude mixtureby chromatography on silica gel eluting with isohexane/EtOAc (19:1 to4:1 gradient) to obtain7-chloro-6-[4-(1-methyl-cyclohexylmethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(101 mg, 39%).

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-[4-(1-methyl-cyclohexylmethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(100 mg, 0.19 mmol). Purify by SCX chromatography eluting with methanoland 3M ammonia in methanol. Use a method similar to the GeneralProcedure 2-6 to obtain the title compound (78 mg, 73%). MS (ES+) m/z:413.2 (M+H)⁺.

EXAMPLES 576-580

Examples 576-580 may be prepared essentially as described in Example 575by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

Yield MS (ES+) Ex. Structure Compound (%) m/z 576

7-Chloro-6-(4-cyclopentyloxy-benzylamino)-2,3,4,5,-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 39 371(M + H)⁺ 577

7-Chloro-6-(3-chloro-4-cyclopentyloxy-benzylamino)-2,3,4,5,-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 6 405(M + H)⁺ 578

7-Chloro-6-[4-(2,2,dimethyl-3-hydroxy-propoxy)-benzylamino)-2,3,4,5,-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 6 389(M + H)⁺ 579

7-Chloro-6-[6-(3,3-dimethyl-butoxy)-pyridin-3-ylmethylamino)-2,3,4,5,-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 50 388(M + H)⁺ 580

7-Chloro-6-[4-(tetrahydro-pyran-4-yloxymethyl)-benzylamino]-2,3,4,5,-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 37 401(M + H)⁺

EXAMPLE 5817-Chloro-4-(4-cyclohexyloxy-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate

Use a method similar to the General Procedure 5-1 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(100 mg, 0.43 mmol) with 4-cyclohexyloxy-benzylamine (58 mg, 0.285 mol)in anhydrous toluene (1 mL). Purify the crude mixture by chromatographyon silica gel eluting with cyclohexane/EtOAc (9:1) to give7-chloro-6-(4-cyclohexyloxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(78 mg, 69%).

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-(4-cyclohexyloxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(237 mg, 0.49 mmol) to obtain the free base of the title compound. Use amethod similar to the General Procedure 2-6 to obtain the title compound(208 mg, 80%). MS (ES+) m/z: 385.2 (M+H)⁺.

EXAMPLE 5827-Chloro-6-[4-(tetrahydro-pyran-4-yloxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate

Example 582 may be prepared essentially as described in Example 581 byusing7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4-(tetrahydro-pyran-4-yloxy)-benzylamine (4% yield, MS (ES+) m/z 387(M+H)⁺).

EXAMPLE 583(±)-7-Chloro-6-[4-(3,3-dimethyl-cyclohexyloxy)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(387 mg, 0.91 mmol) with (±)-4-(3,3-dimethyl-cyclohexyloxy)-benzylamine(233 mg, 1 mmol) in anhydrous 1,4-dioxane (14 mL). Purify the crudemixture by chromatography on silica gel eluting with cyclohexane/EtOAc(19:1 to 1:1 gradient) to obtain(±)-7-chloro-6-[4-(3,3-dimethyl-cyclohexyloxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(227 mg, 50%).

Use a method similar to the General Procedure 1-1 to deprotect(±)-7-chloro-6-[4-(3,3-dimethyl-cyclohexyloxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(220 mg, 0.43 mmol). Purify by SCX chromatography eluting with methanoland 3M ammonia in methanol. Further purify the residue by preparativeHPLC. Use a method similar to the General Procedure 2-1 to obtain thetitle compound (65 mg, 13%). MS (ES+) m/z: 413.2 (M+H)⁺.

EXAMPLE 5847-Chloro-6-(4-cyclohexylthio-pyridin-3-ylmethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Add cesium carbonate (2.04 g, 6.27 mmol), palladium(II) acetate (46 mg,0.209 mmol) and BINAP (195.21 mg, 0.313 mmol) to a solution of7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.79 g, 4.18 mmol) and 5-aminomethyl-2-cyclohexylthio-pyridine (1.11 g,5.02 mmol) in anhydrous toluene (30 mL). Sonicate the resultingsuspension for 30 min then heat at 100° C. for 18 h. Cool the reactionto room temperature. Purify the crude mixture by chromatography onsilica gel eluting with cyclohexane/EtOAc (98:2 to 60:40 gradient) togive7-chloro-6-(4-cyclohexylthio-pyridin-3-ylmethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (1.1 g, 53%).

Use a method similar to the General Procedure 1-1 to deprotect7-chloro-6-(4-cyclohexylthio-pyridin-3-ylmethylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.1 g, 2.21 mmol). Purify by SCX chromatography eluting with methanoland 3M ammonia in methanol. Use a method similar to the GeneralProcedure 2-1 to obtain the title compound as a white solid (0.884 g,77%). MS (ES+) m/z: 402 (M+H)⁺.

EXAMPLE 5856-(4-tert-Butylthio-pyridin-3-ylmethylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-tartrate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(990 mg, 2.32 mmol) with 5-aminomethyl-2-tert-butylthio-pyridine (500mg, 2.55 mmol) in anhydrous toluene (15 mL). Purify the crude mixture bychromatography on silica gel eluting with isohexane/EtOAc (1:0 to 3:1gradient) to obtain6-(4-tert-butylthio-pyridin-3-ylmethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(650 mg, 59%). MS (ES+) m/z: 472 (M+H)⁺.

Use a method similar to the General Procedure 1-2 to deprotect6-(4-tert-butylthio-pyridin-3-ylmethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(650 mg, 1.37 mmol). Purify by SCX chromatography eluting with methanoland 3M ammonia in methanol. Use a method similar to the GeneralProcedure 26 to obtain the title compound (362 mg, 50%). MS (ES+) m/z:376 (M+H)⁺.

EXAMPLES 586-593

Examples 586-593 may be prepared essentially as described in Example 585by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

Yield MS (ES+) Ex. Structure Compound (%) m/z 586

7-Chloro-6-[4-(3,3-dimethylbutylthio)-pyridin-3-ylmethylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate25 404(M + H)⁺ 587

7-Chloro-6-(4-ethoxy-pyridin-3-ylmethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate30 332(M + H)⁺ 588

6-(4-tert-Butylthio-3-chloro-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate37 409(M + H)⁺ 589

7-Chloro-6-(3-chloro-4-cyclohexylmethylthio-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 27 472(M + Na)⁺ 590

7-Chloro-6-(4-cyclohexylmethylthio-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 13 415(M + H)⁺ 591

6-(4-tert-Butoxymethyl-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate16 373(M + H)⁺ 592

7-Chloro-6-(4-cyclopentyloxymethyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 39 385(M + H)⁺ 593

7-Chloro-6-(4-cyclohexylmethyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 33 399(M + H)⁺

EXAMPLE 5947-Chloro-6-[4-(2,2-dimethyl-propoxymethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(426 mg, 1 mmol) with 4-(2,2-dimethyl-propoxymethyl)-benzylamine (230mg, 1.1 mmol) in anhydrous toluene (20 mL). Purify the crude mixture bychromatography on silica gel eluting with isohexane/EtOAc (1:0 to 4:1gradient) to obtain7-chloro-6-[4-(2,2-dimethyl-propoxymethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(380 mg, 79%). MS (ES+) m/z: 483 (M+H)⁺.

Use a method similar to the General Procedure 1-2 to deprotect7-chloro-6-[4-(2,2-dimethyl-propoxyethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(380 mg, 0.88 mmol). Purify by SCX chromatography eluting with methanoland 3M ammonia in methanol. Use a method similar to the GeneralProcedure 2-6 to obtain the title compound (319.2 mg, 70%). MS (ES+)m/z: 387 (M+H)⁺.

EXAMPLE 5957-Chloro-6-(4-cyclohexylthio-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(167 mg, 0.392 mmol) with 4-cyclohexylthio-benzylamine (95.4 mg, 0.431mmol) in anhydrous 1,4-dioxane (5 mL). Purify the crude mixture bychromatography on silica gel eluting with isohexane/EtOAc (1:0 to 13:7gradient) to obtain7-chloro-6-(4-cyclohexylthio-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(155 mg, 79%). MS (ES+) m/z: 519 (M+Na)⁺.

Use a method similar to the General Procedure 1-2 to deprotect7-chloro-6-(4-cyclohexylthio-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(155 mg, 0.312 mmol). Purify by SCX chromatography eluting with methanoland 3M ammonia in methanol. Use a method similar to the GeneralProcedure 2-6 to obtain the title compound (95 mg, 75%). MS (ES+) m/z:401 (M+H)⁺.

EXAMPLES 596-597

Examples 596-597 may be prepared essentially as described in Example 595by using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

Yield MS (ES+) Ex. Structure Compound (%) m/z 596

7-Chloro-6-(4-cyclopentylthio-pyridin-3-ylmethylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate58 388(M + H)⁺ 597

7-Chloro-6-(4-cyclopentylthio-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 58 388(M + H)⁺

EXAMPLE 5987-Chloro-6-(3-chloro-4-ethoxy-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(150 mg, 0.35 mmol) with 4-ethoxy-3-chloro-benzylamine (94.7 mg, 0.51mmol) in anhydrous 1,4-dioxane (10 mL). Purify the crude mixture bychromatography on silica gel eluting with isohexane/EtOAc (100:0 to77:23 gradient) to obtain7-chloro-6-(3-chloro-4-ethoxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(111.3 mg, 68%). MS (ES+) m/z: 483 (M+Na)⁺.

Use a method similar to the General Procedure 1-1, but adding water (10mL) to the 7M ammonia in methanol solution (20 mL), to deprotect7-chloro-6-(3-chloro-4-ethoxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(27 mg, 0.072 mmol) to give the free base of the title compound. Use amethod similar to the General Procedure 2-6 to give the title compoundas a solid (29 mg, 78%). MS (ES+) m/z: 365 (M+H)⁺.

EXAMPLE 5997-Chloro-6-(4-cycloheptyloxy-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Under a nitrogen atmosphere, add 4-cycloheptyloxy-benzylamine (451 mg,2.06 mmol),7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(500 mg, 1.17 mmol), palladium(II) acetate (26 mg, 0.117 mmol), BINAP(110 mg, 0.176 mmol), and cesium carbonate (1.15 g, 3.52 mmol) totoluene (20 mL). Heat the mixture at 90° C. for 12 h. Cool the mixtureto room temperature and dilute with EtOAc (25 mL). Filter the solidsthrough cellulose (20 g) and concentrate in vacuo. Purify the crudemixture by chromatography on silica gel (45 g RediSep column) elutingwith hexane/EtOAc (1:0 to 4:1 gradient over 1 h; 80 mL/min) to provide7-chloro-6-(4-cycloheptyloxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil (384 mg, 61%). MS (APCI) m/z: 495 (M+H)⁺.

Dissolve7-chloro-6-(4-cycloheptyloxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(370 mg, 0.747 mmol) and lithium hydroxide monohydrate (153 mg, 3.73mmol) in methanol (5 mL) and stir for 6 h. Concentrate the mixture invacuo and dissolve the residue in water (20 mL). Extract the mixturewith EtOAc (3×20 mL). Dry the combined organic extracts over Na₂SO₄,filter and concentrate in vacuo. Purify the crude mixture by reversephase HPLC [Phenomonex C18(2) column, 5×25 cm, eluting with a gradientof water/acetonitrile (0.1% TFA in each) (9:1 through 1:9 over 40 min),118 mL/min] to provide the trifluoroacetate salt of the title compound.Dissolve the residue in methanol and elute through an SCX column withsaturated ammonia in methanol to provide the free base of the titlecompound (197 mg, 65%). Use a method similar to the General Procedure2-1 to give the title compound as an off-white solid (250 mg, 100%). MS(APCI) m/z: 399 (M+H)⁺.

EXAMPLE 6007-Chloro-6-(4-cycloheptylthio-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Example 600 may be prepared essentially as described in Example 599 byusing7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4-cycloheptylthio-benzylamine (6% yield, MS (ES+) m/z 415 (M+H)⁺).

EXAMPLE 6017-Chloro-6-(4-cyclohexylmethyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Under a nitrogen atmosphere, add 4-cyclohexylmethyl-benzylaminehydrochloride (352 mg, 1.47 mmol),7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(500 mg, 1.17 mmol), palladium(II) acetate (52.7 mg, 0.235 mmol), BINAP(293 mg, 0.47 mmol) and cesium carbonate (1.53 g, 4.7 mmol) to toluene(20 mL). Heat the mixture at 90° C. for 12 h. Cool the mixture to roomtemperature and dilute with EtOAc (25 mL). Filter the solids throughcellulose (20 g) and concentrate the filtrate in vacuo. Purify the crudemixture by chromatography on silica gel (45 g RediSep column) elutingwith hexane/EtOAc (1:0 to 4:1 gradient over 1 h; 80 mL/min) to provide7-chloro-6-(4-cyclohexylmethyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colorless oil (354 mg, 63%). MS (APCI) m/z: 479 (M+H)⁺.

Dissolve7-chloro-6-(4-cyclohexylmethyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(354 mg, 0.739 mmol) and lithium hydroxide monohydrate (100 mg, 2.43mmol) in methanol (5 mL) and stir overnight. Concentrate the mixture invacuo and dissolve the residue in water (20 mL). Extract the mixturewith EtOAc (3×20 mL). Dry the combined organic extracts over Na₂SO₄,filter, and concentrate in vacuo. Purify the crude mixture bychromatography on silica gel (40 g RediSep column) eluting with agradient of dichloromethane and chloroform/methanol/concentratedammonium hydroxide (80:18:2) over 1 h (80 mL/min) followed by reversephase HPLC [Phenomonex C18(2) column (5×25 cm), eluting withwater/acetonitrile (0.1% TFA in each) (9:1 to 1:9 gradient over 40 min),118 mL/min] to obtain the trifluoroacetate salt of the title compound.Dissolve the residue in methanol and elute through SCX column withsaturated ammonia in methanol to provide7-chloro-6-(4-cyclohexylmethyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(184 mg, 64%). Use a method similar to the General Procedure 2-1 to givethe title compound as a white solid (240 mg, 100%). MS (ES) m/z: 383(M+H)

EXAMPLE 6027-Chloro-6-[4-(2-methyl-butyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Under a nitrogen atmosphere, add 4-(2-methyl-butyl)-benzylamine (450 mg,2.54 mmol),7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(720 mg, 1.7 mmol), palladium(II) acetate (40 mg, 0.17 mmol), BINAP (222mg, 0.34 mmol) and cesium carbonate (1.4 g, 4.3 mmol) to toluene (20mL). Heat the mixture at 95° C. for 12 h. Cool the mixture to roomtemperature and apply the mixture to a silica gel column eluting withhexane/EtOAc (10:1) to provide7-chloro-6-[4-(2-methyl-butyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(450 mg, 59%). MS (ES+) m/z: 453 (M+H)⁺.

Dissolve7-chloro-6-[4-(2-methyl-butyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(450 mg, 1 mmol) and concentrated ammonium hydroxide (5 mL) in methanol(10 mL) and stir overnight. Concentrate the mixture in vacuo. Purify thecrude mixture by SCX chromatography eluting with methanol and 3M ammoniain methanol. Concentrate the product in vacuo and purify the residue byreverse phase HPLC [Phenomonex Luna C18(2), 50 mm×250 mm, eluting withacetonitrile/water with 0.1% TFA (2:3)]. Concentrate in vacuo, basifywith potassium carbonate and extract into dichloromethane. Dry theorganic solution over Na₂SO₄, filter and concentrate in vacuo to providethe free base of the title compound (205 mg, 57%). Use a method similarto the General Procedure 2-1 to give the title compound as a white solid(280 mg, 59%). MS (APCI) m/z: 357 (M+H)⁺.

EXAMPLE 6037-Chloro-6-[4-(3,3-dimethyl-butyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-1 to react7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(623 mg, 1.46 mmol), palladium(II) acetate (33 mg, 0.146 mmol), BINAP(182 mg, 0.292 mmol), 4-(3,3-dimethyl-butyl)-benzylamine (560 mg, 2.93mmol) and cesium carbonate (666 mg, 2.04 mmol) in degassed toluene (40mL). Degas the mixture with vacuum/nitrogen purge and heat to 100° C.for 16 h. Cool the mixture to room temperature, dilute with EtOAc andwash with water. Dry the organic phase over MgSO₄, filter andconcentrate in vacuo. Purify the crude mixture by chromatography onsilica gel eluting with hexane and then hexane/EtOAc (19:1, 9:1) toobtain7-chloro-6-[4-(3,3-dimethyl-butyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas oil (622 mg, 91%). MS (ES+) m/z: 467 (M+H)⁺.

Use a method similar to the General Procedure 1-2, using7-chloro-6-[4-(3,3-dimethyl-butyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine,(448 mg, 0.96 mmol), to give the free base of the title compound as anoil (320 mg, 90%) that was used without further purification. MS (ES+)m/z: 371 (M+H)⁺. Use a method similar to the General Procedure 2-1,using7-chloro-6-[4-(3,3-dimethyl-butyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(315 mg, 0.85 mmol) to give the title compound as a white solid (340 mg,82%). MS (ES+) m/z: 371 (M+H)⁺.

EXAMPLE 6047-Chloro-6-[6-(3,3-dimethyl-butyl)-pyridin-3-yl-methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to the General Procedure 5-2 to react7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(166 mg, 0.39 mmol), tris(dibenzylideneacetone)dipalladium(0) (71 mg,0.078 mmol), BINAP (103 mg, 0.156 mmol),3-aminomethyl-6-(3,3-dimethyl-butyl)-pyridine (150 mg, 0.78 mmol) andcesium carbonate (178 mg, 0.546 mmol) in degassed toluene (20 mL). Degasthe mixture with vacuum/nitrogen purge and heat to 100° C. for 14 h.Cool the mixture to room temperature, dilute with EtOAc and filterthrough Celite®. Purify the crude mixture by chromatography on silicagel eluting with hexane and then hexane/EtOAc (19:1, 9:1 and 4:1) toobtain7-chloro-6-[6-(3,3-dimethyl-butyl)-pyridin-3-yl-methylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas oil (149 mg, 82%). MS (ES+) m/z: 468 (M+H)⁺.

Use a method similar to the General Procedure 1-2, using7-chloro-6-[6-(3,3-dimethyl-butyl)-pyridin-3-yl-methylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(140 mg, 0.29 mmol), to give the free base of the title compound as anoil (96 mg, 86%) that was used without further purification. MS (ES+)m/z: 372 (M+H)⁺. Use a method similar to the General Procedure 2-1,using7-chloro-6-[6-(3,3-dimethyl-butyl)pyridin-3-yl-methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(96 mg, 0.258 mmol) to give the title compound as a solid (19 mg, 94%).MS (ES+) m/z: 372 (M+H)⁺.

EXAMPLES 605-607

Examples 605-607 may be prepared essentially as described in Example 604using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Overall yields and MS (ES+) data are shown inthe Table below.

Yield MS (ES+) Ex. Structure Compound (%) m/z 605

7-Chloro-6-(6-cyclohexylmethyl-pyridin-3-yl-methylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 42 384(M + H)⁺ 606

7-Chloro-6-[5-(3,3-dimethyl-butyl)-pyridin-2-yl-methylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 34 372(M + H)⁺ 607

7-Chloro-6-[4-(1,3,3-trimethyl-butyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate47 385(M + H)⁺

Preparation 320 2-Hydroxymethyl-[1,3,4]-thiadiazole

2-Vinyl-[1,3,4]-thiadiazole: Combine 2-bromo-[1,3,4]-thiadiazole (3.5g±21.2 mmol), tributylvinyltin (6.20 mL, 21.2 mmol) andtetrakis(triphenylphosphine)palladium(0) (735 mg, 0.6 mmol) in anhydroustoluene (141 mL). Heat the mixture at reflux for 18 h. Add methanol anddichloromethane to dissolve the residue and evaporate onto silica gel.Purify the residue by chromatography on silica gel eluting withhexane/EtOAc (1:0 to 1:4 gradient) to give the desired intermediate(0.49 g, 21%). GC-MS m/z: 112 (M⁺).2-Hydroxymethyl-[1,3,4]-thiadiazole: At −10° C. bubble ozone through asolution of 2-vinyl-[1,3,4]-thiadiazole (400 mg, 3.57 mmol) in methanol(18 mL). After 20 min the starting material is consumed. Add then sodiumborohydride (37 mg, 0.98 mmol) and warm to room temperature. Evaporatethe mixture and purify the residue by passage through a pad of silicagel eluting with methanol/dichloromethane (98:2 to 96:4 gradient) togive the title compound (0.24 g, 60%). MS (ES+) m/z: 117 (M+H)⁺.

Preparation 321 5-Chloromethylthiazole

Combine 5-methylthiazole (1.5 g, 15.1 mmol), N-chlorosuccinimide (2.6 g,19.4 mmol) and AIBN (0.26 g, 1.6 mmol) in carbon tetrachloride (15 mL).Reflux under nitrogen for 3 h. Cool the reaction mixture and concentratein vacuo. Purify by chromatography on silica gel eluting withhexane/EtOAc (4:1) to give the title compound as a yellow oil (0.38 g,19%).

Preparation 322 5-Bromomethyl-2-chlorothiazole

5-Chloromethyl-2-chlorothiazole: Combine 5-methyl-2-chlorothiazole (1.05g, 7.5 mmol), NBS (1.7 g, 9.6 mmol) and AIBN (0.12 g, 0.73 mmol) incarbon tetrachloride (10 mL). Reflux under nitrogen for 7 h. Cool andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (9:1) to give the title compound as a yellow oil (0.82g, 51%).

Preparation 323 (±)-1-Methanesulfonyloxy-1-thiazol-2-yl-ethyl

(±)-1-Thiazol-2-yl-ethanol: Add sodium borohydride (357 mg, 9.4 mmol)portionwise, over 5 min, to a solution of 2-acetylthiazole (1.0 g, 7.8mmol) in methanol (25 mL) at 0° C. under a nitrogen atmosphere. Stir themixture for 2 h at room temperature. Concentrate the mixture in vacuo,dilute the residue with brine (30 mL) and adjust the mixture to pH 6with 5N aqueous HCl (10 mL). Extract the mixture with EtOAc (40 mL). Drythe organic layer over Na₂SO₄, filter and concentrate in vacuo to obtainthe desired intermediate (1.0 g, 99%). GC-MS m/z: 129 (M⁺).(±)-1-Methanesulfonyloxy-1-thiazol-2-yl-ethyl: Dissolve1-thiazol-2-yl-ethanol (1.0 g, 7.7 mmol) in dichloromethane (30 mL) andtriethylamine (1.2 mL, 8.5 mmol). Cool the solution to 0° C., then addmethanesulphonyl chloride (690 μl, 8.9 mmol) under a nitrogenatmosphere. Stir the solution for 1.5 h at room temperature, then washwith saturated aqueous NaHCO₃ (30 mL). Dry the organic layer overNa₂SO₄, filter and concentrate in vacuo. Purify the crude mixture bychromatography on silica gel eluting withdichloromethane/hexane/methanol (50:45:5) to obtain the title compound(1.3 g, 81%). GC-MS m/z: 207 (M⁺).

Preparation 324 (±)-1-(3-Fluorophenyl)ethyl bromide

Dissolve (±)-1-(3-fluorophenyl)ethanol (250 mg, 1.786 mmol) in carbontetrachloride (10 mL). Add phosphorus tribromide (0.1 mL, 1.786 mmol) at0° C. and stir the solution at room temperature overnight. Dilute thereaction mixture with dichloromethane and wash with brine. Dry theorganic phase over Na₂SO₄, filter and concentrate in vacuo to obtain thetitle compound (285 mg) that was used without any further purification.

Preparation 325(S)-1-[4-(1-Hydroxyethyl)-phenyl]-3,3-dimethylbutan-1-one

1-[4-(Diethoxymethyl)phenyl]-3,3-dimethylbutan-1-ol: Dissolve1-bromo-4-(diethoxymethyl)-benzene (6.1 g, 23.55 mmol) in anhydrous THF(150 mL) and cool the solution to −78° C. Add n-butyllithium (11.3 mL,28.26 mmol, 2.5M solution in hexane) and stir the mixture for 30 min.Add 3,3-dimethylbutyraldehyde (4.7 mL, 35.33 mmol) and stir the mixturefor 1 h. Add water and EtOAc. Warm the solution to room temperature andextract the aqueous layer three times with EtOAc. Dry the combinedorganic extracts with Na₂SO₄, filter and concentrate in vacuo. Purifythe crude mixture by chromatography on silica gel eluting withhexane/EtOAc (93:7) to give the desired intermediate as a colorless oil(3.8 g, 58%).1-[4-(Diethoxymethyl)-phenyl]-3,3-dimethylbutan-1-one: Dissolve1-[4-(diethoxymethyl)-phenyl]-3,3-dimethylbutan-1-ol (3.8 g, 13.57 mmol)in hexane (50 mL). Add manganese dioxide (3.5 g, 40.71 mmol) and stirthe mixture at 60° C. overnight. Filter the solid and concentrate thefiltrate in vacuo to give the desired intermediate as a colorless oil(3.49 g, 93%).4-(3,3-Dimethyl-butyryl)-benzaldehyde: Dissolve1-[4-(diethoxymethyl)-phenyl]-3,3-dimethylbutan-1-one (3.49 g, 12.55mmol) in acetone (50 mL). Add p-toluenesulfonic acid monohydrate (238mg, 1.256 mmol). Heat the mixture under reflux for 3 h. Concentrate invacuo and partition the residue between water and EtOAc. Extract theaqueous phase three times with EtOAc. Dry the combined organic extractsover Na₂SO₄, filter and concentrate in vacuo. Purify the crude mixtureby chromatography on silica gel eluting with hexane/EtOAc (9:1) to givethe desired intermediate as a colorless oil (1.67 g, 65%).1-[4-(1-Hydroxyethyl)-phenyl]-3,3-dimethylbutan-1-one: Dissolve4-(3,3-dimethyl-butyryl)-benzaldehyde (1.67 g, 8.186 mmol) in anhydrousTHF (20 mL) and cool the solution at −10° C. Add methyl magnesiumbromide (2.7 mL, 8.186 mmol, 3M solution in diethyl ether) and stir themixture for 30 min. Add water at 0° C., dilute with EtOAc and extractthe aqueous layer three times with EtOAc. Dry the combined organicextracts over Na₂SO₄, filter through a short pad of silica gel andconcentrate in vacuo to give the desired intermediate as yellow oil(1.519 g, 84%).(S)-1-[4-(1-hydroxyethyl)-phenyl]-3,3-dimethylbutan-1-one: Dissolve1-[4-(1-hydroxyethyl)-phenyl]-3,3-dimethylbutan-1-one (1.519 g, 6.905mmol) in diisopropyl ether (20 mL). Add 4 Å molecular sieves powder (1.5g), vinyl acetate (2 mL) and lipase Candida Antarctica acrylic resin(150 mg). Stir the mixture at room temperature overnight. Remove thesolid residue by filtration. Concentrate the filtrate in vacuo andpurify the crude mixture by chromatography on silica gel eluting withhexane/EtOAc (4:1) to give(R)-1-(1-acetoxy-ethyl)-4-(3,3-dimethyl-butyryl)-benzene as colorlessoil (0.661 g, 36%) and(S)-1-[4-(1-hydroxyethyl)-phenyl]-3,3-dimethylbutan-1-one as a lightyellow oil (0.737 g, 49%).

Preparation 326 4-Acetyl-benzyl bromide

Heat a mixture of 4′-methylacetophenone (5 g, 37.26 mmol), NBS (6.964 g,39.12 mmol), and AIBN (153 mg, 0.93 mmol) in carbon tetrachloride (120mL) for 14 h at reflux. Cool to ambient temperature and washsequentially with water (100 mL), 1M aqueous HCl (100 mL), 5% aqueousNaHCO₃ (100 mL) and brine (100 mL). Dry the organic phase over Na₂SO₄,filter and concentrate in vacuo. Purify the crude mixture bychromatography on silica gel eluting sequentially with hexane andhexane/EtOAc (19:1, 9:1) to provide the title compound as oil (5.191 g,65%). GC-MS m/z: 213 (M⁺).

Preparations 353-354

The compounds of Preparations 353-354 may be prepared essentially asdescribed in Preparation 326 using 4′-methylpropiophenone (Preparation353) and 4′-methylbutyrophenone (Preparation 354). Yields are shown inthe Table below.

Prep. R Compound Yield (%) 353 Et 4-Propionyl-benzyl bromide 92 354 n-Pr4-Butyryl-benzyl bromide 42

Preparation 329 4-(3-Methyl-butyryl)-benzyl bromide

3,4′-Dimethylbutyrophenone: Add slowly isovaleryl chloride (3.0 g, 24.88mmol) to an ice-cold stirred solution of aluminum trichloride (4.976 g,37.32 mmol) in anhydrous toluene (60 mL). Stir the reaction mixture atambient temperature overnight. Add slowly ice-cold water and extract themixture twice with EtOAc. Dry the combined organic extracts over Na₂SO₄,filter and concentrate in vacuo to give the desired intermediate (4.38g, 100%) that was used without any further purification. GC-MS m/z: 176(M⁺).4-(3-Methyl-butyryl)-benzyl bromide: Heat a mixture of3,4′-dimethylbutyrophenone (3 g, 17.02 mmol), NBS (3.787 g, 16.18 mmol),and AIBN (70 mg, 0.425 mmol) in carbon tetrachloride (80 mL) for 14 h atreflux. Cool to ambient temperature and filter the mixture. Concentratethe filtrate in vacuo. Purify the crude mixture by chromatography onsilica gel eluting sequentially with hexane and hexane/EtOAc (9:1) toprovide the title compound as oil (2.802 g, 65%). GC-MS m/z: 255 (M⁺).

Preparations 356-357

The compounds of Preparations 356-357 may be prepared essentially asdescribed in Preparation 329 using the appropriate acyl chloride.Overall yields and GC-MS data are shown in the Table below.

Yield GC-MS Prep. R Compound (%) m/z 330 i-Propyl 4-Isobutyryl-benzylbromide 32 241 (M)⁺ 357 2-Pyridyl 4-(Pyridine-2-carbonyl)-benzyl  9 276(M)⁺ bromide

Preparation 332 4 (Pyridine-3-carbonyl)-benzyl methanesulfonate

[4-(tert-Butyldimethylsilyloxymethyl)-phenyl]-pyridin-3-yl-methanol:Dissolve 4-(tert-butyldimethylsilyloxymethyl)bromobenzene (1 g, 3.319mmol, prepared by following the procedure described in J. Am. Chem. Soc.1995, 117, 704-714) in anhydrous THF (20 mL). Cool the solution to −78°C., add n-BuLi (4.149 mL, 6.638 mmol, 16M solution in hexane) and stirat this temperature for 1.5 h. Warm to −60° C., stir for an additional30 min and add 3-pyridine carboxaldehyde. Allow the reaction mixture towarm gradually to room temperature and stir overnight. Add brine andextract with EtOAc. Dry the organic phase over Na₂SO₄, filter andconcentrate in vacuo. Purify the crude mixture by chromatography onsilica gel eluting sequentially with hexane and EtOAc to give thedesired intermediate (380 mg, 35%). MS (ES+) m/z: 330 (M+H)*.[4-(tert-Butyldimethylsilyloxymethyl)-phenyl]-pyridin-3-yl-methanone:Add manganese dioxide (1.44 g) to a stirred solution of[4-(tert-butyldimethylsilyloxymethyl)-phenyl]-pyridin-3-yl-methanol (360mg, 0.303 mmol) in anhydrous 1,4-dioxane (25 mL). Heat the mixture to70° C. overnight. Cool the reaction mixture to room temperature, filterthrough Celite® and wash with EtOAc. Concentrate the filtrate in vacuo.Purify the crude mixture by chromatography on silica gel elutingsequentially with hexane and hexane/EtOAc (1:1) to provide the desiredintermediate (233 mg, 65%). GC-MS m/z: 327 (M⁺).4-(Pyridine-3-carbonyl)-benzyl alcohol: Add tetrabutylammonium fluoride(1.37 mL, 1.37 mmol, 1M solution in THF) to a solution of[4-(tert-butyldimethylsilyloxymethyl)-phenyl]-pyridin-3-yl-methanone(225 mg, 0.687 mmol) in anhydrous THF (10 mL) at 0° C. and stir at thistemperature for 1 h. Concentrate the solvent in vacuo and purify thecrude mixture by chromatography on silica gel eluting with EtOAc toprovide the desired intermediate (85 mg, 58%). MS (ES+) m/z: 214 (M+H)⁺.4-(Pyridine-3-carbonyl)-benzyl methanesulfonate: Dissolve4-(pyridine-3-carbonyl)-benzyl alcohol (85 mg, 0.399 mmol) indichloromethane (5 mL). Cool to 0° C. and add triethylamine (0.056 mL,0.438 mmol) and methanesulfonyl chloride (0.033 mL, 0.438 mmol). Allowthe mixture to warm to room temperature and stir for 2 h. Dilute thereaction mixture with dichloromethane and wash with saturated aqueousNaHCO₃. Dry the organic phase over Na₂SO₄, filter and concentrate invacuo to provide the title compound as oil (115 mg, 100%). GC-MS m/z:291 (M⁺).

Preparation 333 4-(Pyridine-4-carbonyl)-benzyl methanesulfonate

The compound of Preparation 333 may be prepared essentially as describedin Preparation 332 using4-(tert-butyldimethylsilyloxymethyl)bromobenzene and 4-pyridinecarboxaldehyde (GC-MS m/z 291 (M)⁺).

Preparation 334 4-(4-Cyano-benzoyl)-benzyl bromide

4-(4-Methyl-benzoyl)-benzonitrile: Suspend 4-cyanobenzoyl chloride (2.0g, 12 mmol) in anhydrous toluene (30 mL). Add aluminum trichloride (2.4g, 18 mmol) in three portions and stir the reaction mixture at ambienttemperature overnight. Cool to 0° C., add carefully water and extractthe mixture twice with EtOAc. Dry the combined organic extracts overNa₂SO₄, filter and concentrate in vacuo to give a solid. Suspend thesolid in diethyl ether and filter to obtain the desired intermediate(1.30 g, 49%) that was used without any further purification. GC-MS m/z:221 (Me).4-(4-Cyano-benzoyl)-benzyl bromide: Heat a mixture of4-(4-methyl-benzoyl)-benzonitrile (300 mg, 1.356 mmol), NBS (386 mg,2.169 mmol), and AIBN (22 mg, 0.136 mmol) in carbon tetrachloride (10mL) for 14 h at reflux. Add additional NBS (121 mg) and AIBN (11 mg) andreflux the mixture for 3 h. Cool the reaction mixture to ambienttemperature and filter the mixture. Concentrate the filtrate in vacuo.Purify the crude mixture by chromatography on silica gel elutingsequentially with hexane and hexane/EtOAc (9:1) to provide the titlecompound as a solid (286 mg, 70%) GC-MS m/z: 300 (M⁺).

Preparation 335 4-(3-Cyano-benzoyl)-benzyl bromide

The compound of Preparation 335 may be prepared essentially as describedin Preparation 334 using 3-cyanobenzoyl chloride (GC-MS m/z 300 (M⁺)).

Preparation 336 2-Methanesulfonyloxymethyl-5-(3-methyl-butyryl)-pyridine

2-(tert-Butyldimethylsilyloxymethyl)-5-(1-hydroxy-3-methyl-butyl)-pyridine:Dissolve 5-bromo-2-(tert-butyldimethylsilyloxymethyl)-pyridine (0.5 g,1.654 mmol, prepared by following the procedure described in J. Med.Chem. 1987, 30, 871-880) in anhydrous THF (12 mL). Cool the solution to−78° C., add n-BuLi (1.14 mL, 1.819 mmol, 1.6M solution in hexane) andstir at this temperature for 40 min. Add slowly isovaleryl aldehyde(0.284 mL, 2.646 mmol) and stir the mixture for 5 h at −78° C. Addadditional isovaleryl aldehyde (0.089 mL, 0.827 mmol) and stir themixture for 1.5 h at −78° C. Add ammonium chloride at −78° C. and warmthe mixture to room temperature. Add EtOAc and extract the aqueous layertwice with EtOAc. Dry the combined organic extracts over Na₂SO₄, filterand concentrate in vacuo. Purify the crude mixture by chromatography onsilica gel eluting with hexane and hexane/EtOAc (4:1) to give thedesired intermediate as oil (330 mg, 64%). GC-MS m/z: 309 (M⁺).2-(tert-Butyldimethylsilyloxymethyl)-5-(3-methyl-butyryl-pyridine: Addmanganese dioxide (1.32 g) to a stirred solution of2-(tert-butyldimethylsilyloxymethyl)-5-(1-hydroxy-3-methyl-butyl)-pyridine(330 mg, 1.066 mmol) in anhydrous 1,4-dioxane (30 mL). Heat the mixtureto 70° C. overnight. Cool the reaction mixture to room temperature,filter through Celite® and wash with EtOAc. Concentrate the filtrate invacuo to provide the desired intermediate as oil (327 mg, 100%). GC-MSm/z: 307 (M>).2-Hydroxymethyl-5-(3-methyl-butyryl)-pyridine: Add tetrabutylammoniumfluoride (2.13 mL, 2.13 mmol, 1M solution in THF) to a solution of2-tert-butyldimethylsilyloxymethyl)-5-(3-methyl-butyryl)-pyridine (330mg, 1.066 mmol) in anhydrous THY (20 mL) at 0° C. and stir at thistemperature for 1 h Concentrate the solvent in vacuo and purify thecrude mixture by chromatography on silica gel eluting with EtOAc toprovide the desired intermediate (327 mg, 100%).2-Methanesulfonyloxymethyl-5-(3-methyl-butyryl)-pyridine: Dissolve2-hydroxymethyl-5-(3-methyl-butyryl)-pyridine (190 mg, 0.98 mmol) indichloromethane (10 mL). Cool to 0° C. and add triethylamine (0.151 mL,1.08 mmol) and methanesulfonyl chloride (0.083 mL, 1.08 mmol). Allow themixture to warm to room temperature and stir for 2 h. Dilute thereaction mixture with dichloromethane and wash with saturated aqueousNaHCO₃. Dry the organic phase over Na₂SO₄, filter and concentrate invacuo to provide the title compound as oil (263 mg, 98%).

Preparation 337 5-Methanesulfonyloxymethyl-2-(3-methyl-butyryl)-pyridine

5-(tert-Butyldimethylsilyloxymethyl)-2-(3-methyl-butyryl)-pyridine:Dissolve 2-bromo-5-(tert-butyldimethylsilyloxymethyl)pyridine (1.99 g,6.583 mmol, prepared by following the procedure described in J. Org.Chem. 2004, 69, 250-262) in anhydrous THF (20 mL). Cool the solution to−78° C., add n-BuLi (4.32 mL, 6.912 mmol, 1.6M solution in hexane) andstir at this temperature for 40 min. Add slowly a solution ofN-methoxy-N-methyl-3-methyl-butyramide (0.955 g, 6.583 mmol) inanhydrous THF (5 mL). Stir the mixture for 2 h at −78° C. and then allowthe mixture to warm to room temperature. Add brine and extract theaqueous layer twice with EtOAc. Dry the combined organic extracts overNa₂SO₄, filter and concentrate in vacuo. Purify the crude mixture bychromatography on silica gel eluting with hexane and hexane/EtOAc (19:1)to give the desired intermediate as yellow oil (890 mg, 44%). GC-MS m/z:307 (M⁺).5-Hydroxymethyl-2-(3-methyl-butyryl)-pyridine: Add tetrabutylammoniumfluoride (5.853 mL, 5.853 mmol, 1M solution in THF) to a solution of5-(tert-butyldimethylsilyloxymethyl)-2-(3-methyl-butyryl)-pyridine (900mg, 2.927 mmol) in anhydrous THF (30 mL) at 0° C. and stir at thistemperature for 2 h. Concentrate the solvent in vacuo and purify thecrude mixture by chromatography on silica gel eluting with hexane andhexane/EtOAc (3:2) to provide the desired intermediate (478 mg, 84%). MS(ES+) m/z: 194 (M+H)⁺.5-Methanesulfonyloxymethyl-2-(3-methyl-butyryl)-pyridine: Dissolve5-hydroxymethyl-2-(3-methyl-butyryl)-pyridine (210 mg, 1.086 mmol) indichloromethane (5 mL). Cool to 0° C. and add triethylamine (0.167 mL,1.195 mmol) and methanesulfonyl chloride (0.093 mL, 1.195 mmol). Allowthe mixture to warm to room temperature and stir for 2 h. Dilute thereaction mixture with dichloromethane and wash with saturated aqueousNaHCO₃. Dry the organic phase over Na₂SO₄, filter and concentrate invacuo to provide the title compound (256 mg, 87%). GC-MS m/z: 271

Preparation 338 1-(3-Chloro-propyl)-1,3-dihydro-indol-2-one

Reflux together oxindole (2.66 g, 20.0 mmol), 1-bromo-3-chloropropane(2.56 mL, 26.0 mmol) and potassium carbonate (5.52 g, 40.0 mmol) inacetonitrile (300 mL) under nitrogen for 16 h. Cool the suspension toroom temperature and filter off the precipitate. Concentrate thefiltrate in vacuo and purify the crude mixture by chromatography onsilica gel eluting with isohexane/EtOAc (1:0 to 3:2 gradient over 40min) to give the title compound as an orange oil (1.65 g, 39%). MS (ES+)m/z: 210 (M+H)⁺.

Preparation 339 1-(2-Chloro-ethyl)-pyrrolidin-2-one

Add thionyl chloride (5 mL) to 1-(2-hydroxy-ethyl)-pyrrolidin-2-one(1.12 mL, 10.0 mmol) dropwise then stir at room temperature for 10 min.Remove solvent in vacuo to give the title compound as an orange oil. MS(ES+) m/z: 148 (M+H)⁺.

Preparation 3401-(3-Bromo-propyl)-3-methyl-1,3-dihydro-benzoimidazol-2-one

Add portion wise 3-methyl-1,3-dihydro-benzoimidazol-2-one (400 mg, 27.0mmol) to a suspension of sodium hydride (1.296 g, 32.4 mmol of 60%dispersion in oil) in anhydrous THF (200 mL) under nitrogen over 15 min,then continue to stir for 30 min. Add 1,3-dibromopropane (11.0 mL, 108mmol) and stir overnight. Then heat at reflux for 3 days. Cool thesuspension to room temperature, pour into brine (400 mL), extract withdiethyl ether (300 mL), dry over MgSO₄ and concentrate in vacuo. Purifyby chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1gradient over 40 min) to give the title compound as a colourless oil(2.15 g, 30%).

Preparations 341-342

The Compound of Preparation 341 may be prepared essentially as describedin Preparation 340 using 3-methyl-1,3-dihydro-benzoimidazol-2-one and1,4-dibromobutane. The compound of Preparation 342 may be preparedessentially as described in Preparation 340 using1-tert-butyl-imidazolidin-2-one and 1-bromo-3-chloropropane. Yields areshown in the Table below.

Yield Prep. Structure Compound (%) 341

1-(4-Bromo-butyl)-3-methyl-1,3-dihydro-benzoimidazol-2-one 56 342

1-tert-Butyl-(3-chloro-propyl)-imidazolidin-2-one  5

Preparation 3431-(3-Bromo-propyl)-3-isopropenyl-1,3-dihydro-benzoimidazol-2-one

Add sodium hydride (600 mg, 16.5 mmol of 60% dispersion in oil) to asolution of 1-isopropenyl-1,3-dihydro-benzoimidazol-2-one (1.311 g, 7.53mmol) in anhydrous DMF (10 mL) under nitrogen at room temperature andstir for 2 h. Add 1-bromo-3-chloropropane (900 μL, 9.03 mmol) and stirfor 3 days. Pour the suspension into water (100 mL), extract withdiethyl ether (2×50 mL). Wash the organic extract with brine (100 mL),dry over MgSO₄ and concentrate in vacuo to give the title compoundimpurified with1-(3-chloro-propyl)-3-isopropenyl-1,3-dihydro-benzoimidazol-2-one (2.03g, 1:1 mixture). MS (ES+) m/z: 251 (M+H)⁺, 293 (M+H)⁺.

Preparation 344 5-(3-Chloropropyl)-3,3-dimethyl-1,3-dihydro-indol-2-one

5-(3-Chloropropionyl)-3,3-dimethyl-1,3-dihydro-indol-2-one: Undernitrogen atmosphere, add chloropropionyl chloride (1.54 mL, 16.13 mmol)to a mixture of 3,3-dimethyl-1,3-dihydro-indol-2-one (2.0 g, 12.41 mmol)and aluminium trichloride (10.26 g, 76.92 mmol) in carbon disulphide (70mL). Heat under reflux for 3 h then allow to cool. Decant off thesolvent and replace it carefully with ice/water (200 mL). Allow theresultant suspension to stir for 20 min before filtering off the productand washing with water (80 mL). Dry in vacuo to obtain the desiredintermediate as a pale brown solid (3.08 g, 99%).5-(3-Chloropropyl)-3,3-dimethyl-1,3-dihydro-indol-2-one: Under nitrogenatmosphere, add 5-(3-chloropropyl)-3,3-diethyl-1,3-dihydro-indol-2-one(3.08 g, 12.24 mmol) to trifluoroacetic acid (9.4 mL, 122.4 mmol). Coolthe resulting suspension to 0° C. and then add triethylsilane (4.5 mL,28.2 mmol) dropwise over 2 min. Heat at 45° C. for 30 min then stir atambient temperature overnight. Pour the reaction mixture onto ice/water(100 mL) and extract with EtOAc (2×100 mL). Dry the combined extractsover MgSO₄, filter and concentrate in vacuo. Purify the crude mixture bychromatography on silica gel eluting with hexane/EtOAc (1:0 to 4:1gradient), to give the title compound as a yellow-orange solid (2.12 g,73%).

Preparation 3453-tert-Butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-9-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

7-Chloro-6-(O-dimethylthiocarbamoyl)-9-fluoro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Heat7-chloro-9-fluoro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.56 g, 1.8 mmol) at reflux in anhydrous 1,4-dioxane (18 mL) withtriethylamine (1.01 mL, 7.2 mmol), N,N-dimethyl-4-aminopyridine (22 mg,0.18 mmol) and dimethylthiocarbamoyl chloride (0.67 g, 5.4 mmol) for 16h. Cool and wash the mixture with 1N aqueous HCl, saturated aqueousNaHCO₃ and brine. Concentrate in vacuo and purify by chromatography onsilica gel eluting with hexane/EtOAc (1:0 to 3:2 gradient) to give thedesired intermediate as a yellow oil that solidifies on standing (0.69g, 96%). MS (ES+) m/z: 399 (M+H)⁺.7-Chloro-6-dimethylcarbamoylthio-9-fluoro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Heat7-chloro-6-(O-dimethylthiocarbamoyl)-9-fluoro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.69 g, 1.73 mmol) in diphenyl ether (6 mL) at 245° C. for 2.5 h. Coolthe mixture and load onto a column of silica gel. Wash diphenyl etheroff with hexane and elute with hexane/EtOAc (1:0 to 3:2 gradient) togive the desired intermediate (0.44 g, 64%). MS (ES+) m/z: 399 (M+H)⁺.3-tert-Butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-9-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Heat7-chloro-6-dimethylcarbamoylthio-9-fluoro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.2 g, 0.5 mmol) in methanol (50 mL) with potassium carbonate (0.28 g,2 mmol) at reflux for 5 h. Cool the mixture, add dropwise a solution ofdi-tert-butyl-dicarbonate (0.22 g, 1.0 mmol) in dichloromethane (20 mL)and stir 17 h. Evaporate the mixture onto silica gel and purify bychromatography eluting with hexane/EtOAc (1:0 to 3:2 gradient) to givethe title compound (0.12 g, 62%). MS (ES+) m/z: 303 (M+H-Boc)⁺.

EXAMPLES 608611

Examples 608-611 may be prepared essentially as described in Example 350by using3-tert-butoxycarbonyl-7-chloro-6-ethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriately substituted chloromethylheterocycle orbromomethylheterocycle. MS (ES+) data are shown in the Table below.

MS (ES+ Ex. SR Compound or APCI+) 608

7-Chloro-6-(benzothiazol-6-yl-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 361(M + H)⁺ 609

7-Chloro-6-(2-phenyl-benzothiazol-6-yl-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 437(M + H)⁺ 610

7-Chloro-6-(2-benzyl-benzothiazol-6-yl-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 451(M + H)⁺ 611

7-Chloro-6-(benzothiophen-6-yl-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride 360(M + H)⁺

EXAMPLE 6127-Chloro-6-([1,3,4]thiadiazol-2-yl-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Stir 2-hydroxymethyl-[1,3,4]-thiadiazole (241 mg, 2.1 mmol) inthionylchloride (5 mL) for 1 h and concentrate in vacuo. Treat thisresidue with the thiolate prepared from3-tert-butoxycarbonyl-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.4 g, 1.04 mmol) and potassium hydroxide (1.37 g, 24.5 mmol) inmethanol (3.5 mL) according to General Procedure 7 to give3-tert-butoxycarbonyl-7-chloro-6-([1,3,4]thiadiazol-2-yl-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.3 g, 70%). Treat an aliquot with trifluoroacetic acid to obtain themass spectrum. MS (ES+) m/z: 312 (M+H)⁺.

Use a method similar to the General Procedure 1-5 to deprotect3-tert-butoxycarbonyl-7-chloro-6-([1,3,4]thiadiazol-2-yl-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(300 mg, 0.73 mmol). Use a method similar to the General Procedure 2-2to give the title compound (208 mg, 82%). MS (ES+) m/z: 312 (M+H)⁺.

EXAMPLE 6137-Chloro-6-(thiazol-5-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to General Procedure 7, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 5-chloromethylthiazole to give, after deprotection and saltformation by methods similar to the General Procedures 1-5 and 2-1, thetitle compound as a white solid (700 mg, 80% overall). HRMS (ES+) m/z:311.0427 (M+H)⁺.

EXAMPLE 6147-Chloro-6-[2-(cyclohexylmethylamino)-thiazol-5-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to General Procedure 7 using3-tert-butoxycarbonyl-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 5-bromomethyl-2-chlorothiazole to give3-tert-butoxycarbonyl-7-chloro-6-(2-chlorothiazol-5-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil (0.9 g, 71%). Dissolve3-tert-butoxycarbonyl-7-chloro-6-(2-chlorothiazol-5-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(120 mg, 0.27 mmol) and cyclohexylmethylamine (1 mL, 7.7 mmol) inabsolute ethanol (1 mL) in a heavy walled Pyrex tube. Heat the reactionin an oil bath at 82° C. for 24 h. Cool the reaction mixture andconcentrate in vacuo. Purify by chromatography on silica gel elutingwith hexane/EtOAc (4:1). Use methods similar to General Procedures 1-5and 2-1 to deprotect and give the title compound as yellow oil (19 mg,26% overall). MS (ES+) m/z: 422 (M+H)⁺.

EXAMPLE 615(−)-7-Chloro-6-[1-(thiazol-2-yl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Add potassium hydroxide (3.9 g, 70 mmol) to a solution of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(900 mg, 2.3 mmol) in methanol (25 mL) under a nitrogen atmosphere. Heatthe mixture at 80° C. for 1.5 h. Cool the mixture to ambienttemperature, then concentrate in vacuo to an oil. Dissolve the oil inEtOAc (50 mL) and wash with saturated aqueous ammonium chloride (30 mL).Separate the organic layer and extract the aqueous layer with EtOAc(3×50 mL). Dry the combined organic extracts over Na₂SO₄, filter andconcentrate in vacuo to an oil (735 mg). Dissolve the oil in anhydrousDMSO (20 mL), then add triethylamine (1.9 mL, 14 mmol) and(±)-1-methanesulfonyloxy-1-thiazol-2-yl-ethyl (1.3 g, 6.3 mmol) atambient temperature under nitrogen. Heat the mixture at 40° C. for 1 h.Cool the reaction to room temperature, then dilute the mixture withhexane/EtOAc (1:1, 50 mL) and wash with aqueous 5% sodium chloride (3×50mL). Separate the organic layer and back extract the aqueous layer withEtOAc (3×50 mL). Combine the organic extracts and concentrate in vacuo.Purify the residue by chromatography on silica gel eluting withhexane/EtOAc (19:1 to 7:3 gradient) to obtain(±)-3-tert-butoxycarbonyl-7-chloro-6-[1-(thiazol-2-yl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(779 mg, 79%). MS (ES+) m/z: 425.0 (M+H)⁺.

Separate(±)-3-tert-butoxycarbonyl-7-chloro-6-[1-(thiazol-2-yl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(770 mg, 1.8 mmol) by normal phase chiral chromatography [Chiralpak AD,8×30 cm, eluting with heptane/3A ethanol (9:1)]. Collect the 2^(nd)eluting isomer of3-tert-butoxycarbonyl-7-chloro-6-[1-(thiazol-2-yl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine{348 mg, 99% ee [Chiralpak AD-H, 4.6×150 mm, eluant heptane/3A ethanol(9:1)]}.

Use a method similar to the General Procedure 1-5 to deprotect3-tert-butoxycarbonyl-7-chloro-6-[1-(thiazol-2-yl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineisomer 2. Purify by chromatography on silica gel eluting withdichloromethane/2M ammonia in methanol (98:2 to 90:10 gradient) to givethe free base of the title compound. Use a method similar to the GeneralProcedure 2-1 to obtain the title compound (350 mg, 96%). MS (ES+) m/z:325.0 (M+H)⁺. [α]²⁰ _(D) −160° (c 0.5, MeOH).

EXAMPLE 6167-Chloro-3-methyl-6-(pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Suspend7-chloro-6-(pyridin-2-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepinehydrochloride in saturated aqueous NaHCO₃ and extract three times withEtOAc. Dry the combined organic extracts over MgSO₄. Filter andconcentrate in vacuo to give the free base as a yellow oil. Combine thefree base (0.2 g, 0.66 mmol), sodium triacetoxyborohydride (0.78 g, 3.7mmol), formaldehyde (37% solution in water, 0.2 mL, 2.7 mmol), andacetic acid (0.45 mL, 7.9 mmol), in 1,2-dichloroethane (5 mL). Stir atroom temperature for 12 h. Concentrate the crude reaction mixture invacuo and partition the residue between EtOAc/water. Separate the layersand extract the aqueous phase with EtOAc (3×30 mL). Wash the combinedorganic extracts with 1M aqueous NaOH. Dry over MgSO₄, filter andconcentrate in vacuo. Purify the crude mixture by chromatography onsilica gel eluting with 2M ammonia in methanol/dichloromethane (4:96).

Use a method similar to the General Procedure 2-1 to give the titlecompound as a sticky glass (140 mg, 48%). HRMS (ES+) m/z: 319.1029(M+H)⁺.

EXAMPLES 617 AND 6187-Chloro-6-(2,2,2-trifluoro-1-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride Isomer 1 and7-Chloro-6-(2,2,2-trifluoro-1-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride Isomer 2

Separate the two enantiomers of(±)-7-chloro-6-(2,2,2-trifluoro-1-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepinehydrochloride by normal phase chiral chromatography (Chiralpak AD, 2×25cm, eluting with heptane/ethanol (85:15) with 0.2% DMEA).

Subject the first eluting isomer to the General Procedure 1-4 to obtain7-chloro-6-(2,2,2-trifluoro-1-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepinehydrochloride isomer 1 [99% ee (Chiralpak AD-H, 4.6×150 mm, eluting withheptane/ethanol (85:15) with 0.2% DMEA, flow rate 0.6 mL/min)]. MS (ES+)m/z: 373.1 (M+H)⁺.

Subject the second eluting isomer to the General Procedure 14 to obtain7-chloro-6-(2,2,2-trifluoro-1-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepinehydrochloride isomer 2 [99% ee (Chiralpak AD-H, 4.6×150 mm, eluting withheptane/ethanol (85:15) with 0.2% DMEA, flow rate 0.6 mL/min)]. MS (ES+)m/z 373.1 (M+H)⁺.

EXAMPLE 619(−)-7-Chloro-6-(1-pyridin-2-yl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Separate the two enantiomers of(±)-7-chloro-6-(1-pyridin-2-yl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepinehydrochloride by normal phase chiral chromatography (Chiralcel OJ, 8×33cm, eluting with heptane/methanol/3A ethanol (85:10:5) with 0.2% DMEA).

Subject the second eluting isomer to the General Procedure 1-4 to obtainthe title compound [93% ee (Chiralcel OJ, 4.6×250 mm, eluting withheptane/methanol/3A ethanol (90:5:5) with 0.2% DMEA, flow rate 0.6mL/min)]. MS (ES+) m/z: 333.1 (M+H)⁺. [α]²⁰ _(D) −240.6° (c 0.5, MeOH).

EXAMPLE 620(±)-7-Chloro-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Dissolve3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(415 mg, 1.08 mmol) in methanol (20 mL) and add potassium hydroxide(1.938 g, 34.53 mmol). Heat at 60° C. for 4 h. Cool the reaction mixtureto ambient temperature, add aqueous saturated ammonium chloride andconcentrate in vacuo. Partition the residue between EtOAc and water. Drythe organic phase over anhydrous Na₂SO₄ and concentrate in vacuo to give3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.34 g, 1.086 mmol). Dissolve the crude3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.34 g, 1.086 mmol) in anhydrous DMF (10 mL), add sodium hydride (65mg, 1.63 mmol, 60% in mineral oil) and stir the mixture for 5 min. Add asolution of (±)-1-(4-fluorophenyl)ethyl bromide (332 mg, 1.63 mmol) inanhydrous DMF (5 mL) and heat the solution at 45° C. overnight. Cool toambient temperature, add water and extract the aqueous phase twice withEtOAc. Dry the combined organic extracts over anhydrous Na₂SO₄, filterand concentrate in vacuo. Purify the crude mixture by chromatography onsilica gel eluting with hexane and hexane/EtOAc (19:1 and 9:1) to give(±)-3-tert-butoxycarbonyl-7-chloro-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas oil (397 mg, 84%). MS (ES+) m/z: 336 (M+H-Boc)⁺.

Use a method similar to the General Procedure 1-4 to deprotect(±)-3-tert-butoxycarbonyl-7-chloro-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(47 mg, 0.108 mmol) and give the title compound as a solid (39 mg, 99%).MS (ES+) m/z: 336 (M+H)⁺.

EXAMPLES 621-622

Examples 621-622 may be prepared essentially as described in Example 620using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate alkyl bromide. Overall yields and MS (ES+) data areshown in the Table below.

Yield MS (ES+) Ex. Structure Compound (%) m/z 621

(±)-7-Chloro-6-[1-(3-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride75 336(M + H)⁺ 622

(±)-7-Chloro-6-(1-methyl-2-phenyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride80 332(M + H)⁺

EXAMPLES 623 AND 6247-Chloro-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate Isomer 1 and7-chloro-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate Isomer 2

Separate the two enantiomers of(±)-3-tert-butoxycarbonyl-7-chloro-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineby chiral HPLC (Chiralcel OJ-H 4.6×150 mm column, eluting with methanolat 0.6 mL/min).

Subject Isomer 1 (t_(R)=7.3 min, ee >99.9%) to the General Procedure 2-1to afford7-chloro-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate isomer 1 as a white solid. MS (ES+) m/z 336 (M+H)⁺.

Subject Isomer 2 (t_(R)=12.9 min, ee=99.9%) to the General Procedure 2-1to afford7-chloro-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate isomer 2 as a white solid. MS (ES+) m/z 336 (M+H)⁺.

EXAMPLES 625 AND 626

7-Chloro-6-[1-(3-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate Isomer 1 and7-chloro-6-[1-(3-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate Isomer 2

Separate the two enantiomers of(±)-3-tert-butoxycarbonyl-7-chloro-6-[1-(3-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineby chiral HPLC (Chiralcel OJ-H 4.6×150 mm column, eluting with methanolat 0.6 mL/min).

Subject Isomer 1 (t_(R)=5.4 min, ee >99.9%) to the General Procedure 2-1to afford7-chloro-6-[1-(3-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate isomer 1 as a white solid. MS (ES+) m/z 336 (M+H)⁺.

Subject Isomer 2 (t_(R)=11.2 min, ee=99.7%) to the General Procedure 2-1to afford7-chloro-6-[1-(3-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepinesuccinate isomer 2 as a white solid. MS (ES+) m/z 336 (M+H)⁺.

EXAMPLE 627(S)-7-Chloro-6-{1-[4-(3,3-dimethylbutyryl)-phenyl]-ethylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Heat the mixture of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(310 mg, 0.807 mmol) and potassium hydroxide (1.45 g, 25.83 mmol) inmethanol (5 mL) at 50° C. for 3 h. Cool the reaction mixture to roomtemperature and dilute with saturated aqueous NH₄Cl and EtOAc. Separatethe layers and extract the aqueous layer three times with EtOAc. Dry thecombined organic extracts over Na₂SO₄, filter and concentrate in vacuo.Dissolve the crude3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepinein anhydrous DMF (2 mL) and cool at 0° C. Add sodium hydride (21 mg,0.888 mmol) and a solution of(R)-1-[4-(1-bromoethyl)-phenyl]-3,3-dimethylbutan-1-one {prepared by themixture of (S)-1-[4-(1-hydroxyethyl)-phenyl]-3,3-dimethylbutan-1-one(213 mg, 0.969 mmol), triphenylphosphine (296 mg, 1.130 mmol) and NBS(201 mg, 1.13 mmol) in anhydrous THF (5 mL) at 0° C. and then roomtemperature}. Stir the mixture at 0° C. for 30 min and quench withwater. Dilute with EtOAc and extract the aqueous layer three times withEtOAc. Dry the combined organic extracts over Na₂SO₄, filter andconcentrate in vacuo. Purify the crude mixture by chromatography onsilica gel eluting with hexane/EtOAc (85:15) to give(S)-3-tert-butoxycarbonyl-7-chloro-6-{1-[4-(3,3-dimethylbutyryl)-phenyl]-ethylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepineas yellow oil (197 mg, 47%).

Use a method similar to the General Procedure 1-4, using(S)-3-tert-butoxycarbonyl-7-chloro-6-{1-[4-(3,3-dimethylbutyryl)-phenyl]-ethylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepine(197 mg, 0.382 mmol) to give the title compound as a white solid (161mg, 93%). MS (ES+) m/z: 416 (M+H)⁺; ee=92%, t_(R)=11.27 min (ChiralcelOJ, 4.6×250 mm, 45° C., eluent: 20% isopropanol with 0.05% triethylaminein SFC, flow rate 2 mL/min, UV detector at 234 nm).

EXAMPLE 628(S)-7-Chloro-6-(1-phenyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Example 628 may be prepared essentially as described in Example 627using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand (R)-(1-bromo-ethyl)-benzene (64% yield, MS (ES+) m/z 318 (M+H)⁺).

EXAMPLE 6296-(4-Acetyl-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Use a method similar to the General Procedure 7 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.521 mmol) with 4-acetylbenzyl bromide (555 mg, 2.605 mmol).Purify the crude mixture by chromatography on silica gel elutingsequentially with hexane and hexane/EtOAc (9:1, 4:1) to obtain6-(4-acetyl-benzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(190 mg, 82%).

Use a method similar to the General Procedure 1-4 to deprotect6-(4-acetyl-benzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine(170 mg, 0.381 mmol) and give the title compound as a white solid (140mg, 96%). MS (ES+) m/z: 346 (M+H)⁺.

EXAMPLES 630-634

Examples 630-634 may be prepared essentially as described in Example 629using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate benzyl bromide. Overall yields and MS (ES+) data areshown in the Table below.

Yield MS (ES+) Ex. R Compound (%) m/z 630 Ethyl7-Chloro-6-(4-propionyl-benzoyl- 87 360thio)-2,3,4,5-tetrahydro-1H-benzo[d] (M + H)⁺ azepine Hydrochloride 631n- 6-(4-Butyryl-benzylthio)-7-chloro- 81 374 Propyl2,3,4,5-tetrahydro-1H-benzo[d] (M + H)⁺ azepine Hydrochloride 632i-Propyl 7-Chloro-6-(4-isobutyryl-benzylthio)- 69 3742,3,4,5-tetrahydro-1H-benzo[d] (M + H)⁺ azepine Hydrochloride 633i-Butyl 7-Chloro-6-[4-(3-methyl-butyryl)- 68 388benzylthio]-2,3,4,5-tetrahydro-1H- (M + H)⁺ benzo[d]azepineHydrochloride 634 2- 7-Chloro-6-[4-(pyridine-2-carbonyl)- 38 409 Pyridylbenzylthio]-2,3,4,5-tetrahydro-1H- (M + H)⁺ benzo[d]azepineHydrochloride

EXAMPLE 6357-Chloro-6-[4-(pyridine-3-carbonyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Dissolve3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(150 mg, 0.39 mmol) in methanol (10 mL) and add potassium hydroxide (0.7g, 12.47 mmol). Heat at 60° C. for 4 h. Cool the reaction mixture toambient temperature, add aqueous saturated ammonium chloride andconcentrate in vacuo. Partition the residue between EtOAc and water. Drythe organic phase over anhydrous Na₂SO₄ and concentrate in vacuo to give3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.12 g). Dissolve the crude3-tert-butoxycarbonyl-7-chloro-6mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.12 g, 5.2 mmol) in anhydrous DMSO (6 mL) and add triethylamine (0.325mL, 2.34 mmol) and 4-(pyridine-3-carbonyl)-benzyl methanesulfonate (114mg, 0.39 mmol). Heat the solution at 40° C. overnight. Cool to ambienttemperature, dilute the mixture with hexane/EtOAc (1:1, 100 mL), andwash the organic solution sequentially with brine and ice-cold water.Dry the organic layer over anhydrous Na₂SO₄, filter and concentrate invacuo. Purify the crude mixture by chromatography on silica gel elutingwith hexane and hexane/EtOAc (1:1) to give3-tert-butoxycarbonyl-7-chloro-6-[4-(pyridine-3-carbonyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas oil (123 mg, 64%).

Use a method similar to the General Procedure 1-4 to deprotect3-tert-butoxycarbonyl-7-chloro-6-[4-(pyridine-3-carbonyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(113 mg, 0.22 mmol) and give the title compound as a solid (105 mg,99%). MS (ES+) m/z: 409 (M+H)⁺.

EXAMPLES 636-638

Examples 636-638 may be prepared essentially as described in Example 635using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate methanesulfonate. Overall yields and MS (ES+) dataare shown in the Table below.

Yield MS (ES+) Ex. Structure Compound (%) m/z 636

7-Chloro-6-[4-(pyridine-4-carbonyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride39 409(M + H)⁺ 637

7-Chloro-6-[5-(3-methyl-butyryl)-pyridin-2-yl-methylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride69 389(M + H)⁺ 638

7-Chloro-6-[6-(3-methyl-butyryl)-pyridin-3-yl-methylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride57 389(M + H)⁺

EXAMPLE 6397-Chloro-6-[4-(3-cyanobenzoyl)-benzylthio]-3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Dissolve3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.52 mmol) in methanol (12 mL) and add potassium hydroxide(0.935 g, 16.66 mmol). Heat at 60° C. for 4 h Cool the reaction mixtureto ambient temperature, add aqueous saturated ammonium chloride andconcentrate in vacuo. Partition the residue between EtOAc and water. Drythe organic phase over anhydrous Na₂SO₄ and concentrate in vacuo to give3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.16 g, 5.2 mmol). Dissolve the crude3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.16 g, 0.52 mmol) in anhydrous DMSO (5 mL) and add triethylamine(0.435 mL, 3.12 mmol) and 4-(3-cyano-benzoyl)benzyl bromide (289 mg,0.96 mmol). Heat the solution at 40° C. overnight. Cool to ambienttemperature, dilute the mixture with hexane/EtOAc (1:1, 100 mL), andwash the organic solution sequentially with brine and ice-cold water.Dry the organic layer over anhydrous Na₂SO₄, filter and concentrate invacuo. Purify the crude mixture by chromatography on silica gel elutingwith hexane and hexane/EtOAc (9:1, 4:1) to give3-tert-butoxycarbonyl-7-chloro-6-[4-(3-cyanobenzoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas oil (212 mg, 77%).

Use a method similar to the General Procedure 1-4 to deprotect3-tert-butoxycarbonyl-7-chloro-6-[4-(3-cyanobenzoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.37 mmol) and give the title compound as a solid (136 mg,77%). MS (ES+) m/z: 433 (M+H)⁺.

EXAMPLE 6407-Chloro-6-[4-(4-cyanobenzoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

20. Example 640 may be prepared essentially as described in Example 639using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 4-(4-cyano-benzoyl)benzyl bromide (49% yield, MS (ES+) m/z 433(M+H)⁺).

EXAMPLE 6417-Chloro-6-(4-tert-butylthiocarbamoyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Combine7-chloro-6-(4-tert-butylcarbamoyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(53 mg, 0.13 mmol) with2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(Lawesson's reagent) (53 mg, 0.13 mmol) in anhydrous 1,4-dioxane (1 mL)in a sealed tube and heat at 100° C. for 2 h. Cool the reaction mixtureto room temperature, concentrate in vacuo and purify the residue by SCXchromatography to obtain7-chloro-6-(4-tert-butylthiocarbamoyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil. Purify by reverse phase preparative HPLC [ZorbaxSB-Phenyl 21.2×250 mm, 5 micron, 22 mL/min of 0.1% aqueousHCl/acetonitrile (9:1 to 1:9) over 30 min, detector at 230 nm].

Use a method similar to the General Procedure 2-2 to obtain the titlecompound as a yellow solid (36 mg, 58%). MS (ES+) m/z: 419 (M+H)⁺.

EXAMPLE 6427-Chloro-6-[4-(4-fluorobenzylthiocarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Combine7-chloro-6-[4-(4-fluorobenzylcarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(23 mg, 0.05 mmol) with2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(Lawesson's reagent) (23 mg, 0.05 mmol) in anhydrous 1,4-dioxane (1 mL)in a sealed tube and heat at 100° C. for 2 h Cool the reaction mixtureto room temperature, concentrate in vacuo and purify the residue by SCXchromatography to obtain7-chloro-6-[4-(4-fluorobenzylthiocarbamoyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow oil.

Use a method similar to the General Procedure 2-1 to obtain the titlecompound as a white solid (10 mg, 42%). MS (ES+) m/z: 471 (M+H)⁺.

EXAMPLE 6437-Chloro-6-(6-cyclohexylamino-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to General Procedure 7, using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(2 g, 5.2 mmol) and 2-chloro-5-(chloromethyl)pyridine (843 mg, 5.2 mmol)to give3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(2.2 g, 95%). MS (ES+) m/z: 439.1 (M+H)⁺.

Slurry palladium(II) acetate (434 mg, 1.9 mmol), BINAP (1.2 g, 1.9mmol), sodium-tert-butoxide (644 mg, 6.7 mmol), cyclohexylamine (1.4 g,14.4 mmol) and3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(2.1 g, 4.8 mmol) in anhydrous toluene (70 mL). Degas the slurry underhouse vacuum, then buble nitrogen. Heat the mixture to 95° C. for 16 hunder a nitrogen atmosphere. Cool the mixture to room temperature,dilute with EtOAc (50 mL) and filter through Celite®. Concentrate thefiltrate to an oil and purify by chromatography on silica gel elutingwith hexane/EtOAc (19:1 to 13:7 gradient) to obtain3-tert-butoxycarbonyl-7-chloro-6-(6-cyclohexylamino-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(800 mg, 33%). MS (ES+) m/z: 502.2 (M+H)⁺.

Use a method similar to the General Procedure 1-5 to deprotect3-tert-butoxycarbonyl-7-chloro-6-(6-cyclohexylamino-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(790 mg, 1.6 mmol). Purify by chromatography on silica gel eluting withdichloromethane/2M ammonia in methanol (99:1 to 95:5 gradient) to givethe free base of the title compound. Use a method similar to the GeneralProcedure 2-1 to obtain the title compound (670 mg, 82%). MS (ES+) m/z:402.1 (M+H)⁺.

EXAMPLE 6447-Chloro-6-(6-trifluoroethylamino-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Example 644 may be prepared essentially as described in Example 643 byusing3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2,2,2-trifluoroethylamine (10% yield, MS (ES+) m/z 502.2 (M+H)⁺).

EXAMPLE 6457-Chloro-6-(6-cyclohexylmethylamino-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Add cyclohexylmethylamine (3 mL) to a flask containing3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(340 mg, 0.8 mmol) and ammonium chloride (50 mg, 0.92 mmol). Heat thecontents in a sealed flask at 170° C. for 7 h. Cool the flask to roomtemperature, dilute with EtOAc (50 mL) and wash with water (20 mL).Collect the organic layer and concentrate in vacuo. Purify the residueby chromatography on silica gel eluting with hexane/EtOAc (19:1 to 4:1gradient) to obtain3-tert-butoxycarbonyl-7-chloro-6-(6-cyclohexylmethylamino-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(160 mg, 40%).

Use a method similar to the General Procedure 1-5 to deprotect3-tert-butoxycarbonyl-7-chloro-6-(6-cyclohexylmethylamino-pyridin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by chromatography on silica gel eluting with dichloromethane/2Mammonia in methanol (99:1, 98:2, 96:4 gradient) to give the free base ofthe title compound. Use a method similar to the General Procedure 2-1 toobtain the title compound (115 mg, 70%). MS (ES+) m/z: 416.0 (M+H)⁺.

EXAMPLE 6467-Chloro-6-(2,2-difluoro-2-phenyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Dissolve3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.52 mmol) in methanol (10 mL) and add potassium hydroxide(0.934 g, 16.64 mmol). Heat at 60° C. for 4 h. Cool the reaction mixtureto ambient temperature, add aqueous saturated ammonium chloride andconcentrate in vacuo. Partition the residue between EtOAc and water. Drythe organic phase over anhydrous Na₂SO₄ and concentrate in vacuo to give3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.163 g). Dissolve the crude3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.163 g, 0.52 mmol) in anhydrous DMSO (5 mL) and add triethylamine(0.43 mL, 3.12 mmol) and 2,2-difluoro-2-phenylethyltrifluoromethanesulfonate (151 mg, 0.52 mmol). Heat the solution at 40°C. overnight. Cool to ambient temperature, add water and extract theaqueous phase twice with EtOAc. Dry the combined organic extracts overanhydrous Na₂SO₄, filter and concentrate in vacuo. Purify the crudemixture by chromatography on silica gel eluting with hexane andhexane/EtOAc (19:1, 9:1 and 4:1) to give3-tert-butoxycarbonyl-7-chloro-6-(2,2-difluoro-2-phenyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas oil (132 mg, 56%).

Use a method similar to the General Procedure 1-4 to deprotect3-tert-butoxycarbonyl-7-chloro-6-(2,2-difluoro-2-phenyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(132 mg, 0.29 mmol) and give the title compound as a solid (111 mg,98%). MS (ES+) m/z: 354 (M+H)⁺.

EXAMPLE 6477-Chloro-6-(2,2-difluoro-2-pyridin-2-yl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineHydrochloride

Example 647 may be prepared essentially as described in Example 646using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand 2,2-difluoro-2-pyridin-2-yl-ethyl trifluoromethanesulfonate(prepared by following the procedure described in J. Med. Chem. 2003,46, 461-473) (66% yield, MS (ES+) m/z 355 (M+H)⁺).

EXAMPLE 6487-Chloro-6-[3-(2-oxo-2,3-dihydro-indol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Add potassium hydroxide (899 mg, 16.64 mmol) in one portion to asolution of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, 0.52 mmol) in methanol (10 mL). Heat the reaction to 50° C.under nitrogen for 24 h, then cool to room temperature and add1-(3-chloro-propyl)-1,3-dihydro-indol-2-one (217 mg, 1.04 mmol). Stirthe reaction at room temperature for 4 days. Remove solvents in vacuo,add dichloromethane (20 mL) and water (20 mL). Remove the organic layerand dry using an ISCO® phase separator then concentrate in vacuo to give3-tert-butoxycarbonyl-7-chloro-6-[3-(2-oxo-2,3-dihydro-indol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas orange powder. MS (ES+) m/z: 509 (M+Na)⁺.

Dissolve3-tert-butoxycarbonyl-7-chloro-6-[3-(2-oxo-2,3-dihydro-indol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(0.52 mmol) in dichloromethane (10 mL), then add TFA (2 mL) dropwise andstir for 2 h. Remove solvents in vacuo, then free base using an SCXcolumn, eluting with 7M ammonia in methanol. Purify using UV-guidedreverse phase HPLC [Supelco Discovery C18 column (21.2×100 mm, 5 μmpacking), 20 mL/min flow rate, eluting with water/acetonitrile/aceticacid gradient over 15 min, fraction collection triggered using UVdetector (220 and 254 nm)] followed by SCX column, eluting with 7Mammonia in methanol, then Mass-guided reverse phase HPLC [SupelcoDiscovery C18 column (21.2×100 mm, 5 ppm packing), 25 mL/min flow rate,eluting with water/acetonitrile/acetic acid gradient over 12 min,fraction collection triggered by Electrospray MS] and SCX column.Concentrate in vacuo, then use a method similar to the General Procedure2-1 and freeze dry to give the title compound as a light pink solid (51mg, 19%). MS (ES+) w/z: 387 (M+H)⁺.

EXAMPLES 649650

Examples 649-650 may be prepared essentially as described in Example 648using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriately substituted alkyl chloride. Overall yields and MS(ES+) data are shown in the Table below.

Yield MS (ES+) Ex. Structure Compound (%) m/z 649

7-Chloro-6-[2-(2-oxo-pyrrolidin-1-yl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 71 325(M + H)⁺ 650

7-Chloro-6-[2-(3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 32 401(M + H)⁺

EXAMPLE 6517-Chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Add potassium hydroxide (170 mg, 3.03 mmol) in one portion to a solutionof3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(187 mg, 0.49 mmol) in methanol (10 mL). Heat the reaction at refluxunder nitrogen overnight. Then add further portion of KOH (867 mg, 15.45mmol) and heat at reflux for 3 h. Then cool to room temperature and add1-(3-bromo-propyl)-1,3-dihydro-3,3-dimethyl-indol-2-one (274 mg, 0.97mmol, prepared by following the procedure described in Perkin 1 2000,769-774). Stir the reaction at room temperature overnight. Removesolvents in vacuo, add water and extract with diethyl ether (2×50 mL).Combine the organic extracts, wash with water (2×50 mL) and brine (50mL). Dry over MgSO₄ and concentrate in vacuo. Purify by chromatographyon silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40min) to give3-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a colourless oil (330 mg), 50% contaminated with1-(3-methoxypropyl)-1,3-dihydro-3,3-dimethyl-indol-2-one. MS (ES+) m/z:537 (M+Na)⁺.

Dissolve3-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(240 mg, 0.52 mmol) in dichloromethane (10 mL), then add TFA (1 mL)dropwise and stir at room temperature overnight. Remove solvents invacuo to give a straw coloured oil (580 mg), then free base using an SCXcolumn, eluting with 7M ammonia in methanol. Concentrate in vacuo, thenuse a method similar to the General Procedure 2-1 and freeze dry to givethe title compound as a solid (196 mg, 82%). MS (ES+) m/z: 415 (M+H)⁺.

EXAMPLES 652-654

Examples 652-654 may be prepared essentially as described in Example 651using3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate alkyl bromide. Examples 655-657 may be preparedessentially as described in Example 651 using the appropriate alkylchloride. Overall yields and MS (ES+) data are shown in the Table below.

Yield MS (ES+) Ex. Structure Compound (%) m/z 652

7-Chloro-6-[4-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-butylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 71 414(M + H)⁺ 653

7-Chloro-6-[3-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 31 402(M + H)⁺ 654

7-Chloro-6-[4-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-butylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 31 416(M + H)⁺ 655

7-Chloro-6-[3-(3-methyl-2-oxo-imidazolidin-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 29 354(M + H)⁺ 656

7-Chloro-6-[3-(3-tert-butyl-2-oxo-imidazolidin-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 31 396(M + H)⁺ 657

7-Chloro-6-[3-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 66 400(M + H)⁺

EXAMPLE 6587-Chloro-6-[3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Add potassium hydroxide (933 mg, 16.6 mmol) in one portion to a solutionof3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(200 mg, u (152 mmol) in methanol (10 mL). Heat the reaction at refluxunder nitrogen 4 h. Then cool to room temperature and add1-(3-bromo-propyl)-3-isopropenyl-1,3-dihydro-benzoimidazol-2-one (142mg, 0.52 mmol). Stir the reaction at room temperature overnight. Removesolvents in vacuo, extract into diethyl ether (2×50 mL), wash with water(2×50 mL) and brine (50 mL). Dry over MgSO₄, filtrate and concentrate invacuo to give3-tert-butoxycarbonyl-7-chloro-6-[3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (209 mg, 76%). MS (ES+) m/z: 550 (M+Na)⁺.

Dissolve3-tert-butoxycarbonyl-7-chloro-6-[3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(209 mg, 0.396 mmol) in dichloromethane (10 mL), then add TFA (0.5 mL)dropwise and stir at room temperature overnight. Remove solvents invacuo then free base using an SCX column, eluting with 7M ammonia inmethanol. Concentrate in vacuo, then use a method similar to the GeneralProcedure 2-1 and freeze dry to give the title compound as a solid (140mg, 70%). MS (ES+) m/z: 388 (M+H)⁺.

EXAMPLE 6597-Chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Under nitrogen atmosphere, add potassium hydroxide (138 mg, 2.46 mmol)to a stirred solution of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(375 mg, 0.97 mmol) in methanol (10 mL). Heat under reflux for 2 h thenadd further potassium hydroxide (159 mg, 2.83 mmol) and continue heatingunder reflux for another 6 h. Cool the reaction mixture and add dropwisevia cannula a solution of5-(3-chloropropyl)-3,3-dimethyl-1,3-dihydro-indol-2-one (245 mg, 1.03mmol) in methanol (10 mL). Stir at ambient temperature overnight thenheat at 50° C. for 5 h. Add potassium iodide (186 mg, 1.12 mmol) to thereaction mixture and then heat under reflux for 5 h. Concentrate invacuo and partition the residue between water (100 mL) and EtOAc (50mL). Extract the aqueous phase with EtOAc (2×50 mL). Wash the combinedextracts with brine (50 mL), dry over MgSO₄, filter and concentrate invacuo to obtain the crude mixture as a yellow oil. Dilute this oil withdichloromethane then re-concentrate in vacuo and repeat until a solidremains. Dry the solid in a vacuum oven to give3-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a yellow solid (481 mg) that was used without further purification.MS (ES+) m/z: 537 (M+Na)⁺.

Add trifluoroacetic acid (0.2 mL, 2.6 mmol) to a solution of3-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(257 mg, 0.5 mmol) in dichloromethane (5 mL) then stir at ambienttemperature over the weekend. Concentrate in vacuo. Dissolve the residuein methanol and load onto an SCX column. Elute with methanol followed by7M ammonia in methanol. Collect the basic fraction and concentrate invacuo. Purify the residue by prep-LCMS [Supelco Discovery C18 column(21.2×100 mm, 5 μm packing), 25 mL/min flow rate, eluting with awater/acetonitrile gradient containing acetic acid as modifier over 12min, fraction collection triggered by Electrospray MS] to give7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a white solid (101 mg, 25% over 2 steps). MS (ES+) m/z: 415 (M+H)⁺.

Dissolve7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(101 mg, 0.24 mmol) in a mixture of diethyl ether (3 mL) and methanol (2mL). Add succinic acid (28.7 mg, 0.24 mmol) and allow the resultantsuspension to stir at ambient temperature for 2 h. Concentrate in vacuoand dry the residue in a vacuum oven to afford the title compound as awhite solid. MS (ES+) m/z: 415 (M+H)⁺.

EXAMPLE 6607-Chloro-6-(N-phenylcarbamoyl-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Add potassium hydroxide (890 mg, 15 mmol) in one portion to a solutionof3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(180 mg, 0.47 mmol) in methanol (10 mL). Heat the reaction at refluxunder nitrogen 3 h. Then cool to room temperature, add2-chloro-N-phenyl-acetamide (79 mg, 0.47 mmol) and stir overnight.Remove solvents in vacuo, extract into diethyl ether (2×50 mL), washwith water (2×50 mL) and brine (50 mL). Dry over MgSO₄, filtrate andconcentrate in vacuo to give3-tert-butoxycarbonyl-7-chloro-6-(N-phenylcarbamoyl-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas a clear oil (210 mg, 100%). MS (ES+) m/z: 460 (M+Na)⁺.

Dissolve3-tert-butoxycarbonyl-7-chloro-6-(N-phenylcarbamoyl-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(210 mg, 0.47 mmol) in dichloromethane (10 mL) then add TFA (0.5 mL)dropwise and stir at room temperature for 3 days. Remove solvents invacuo then free base using an SCX column, eluting with 7M ammonia inmethanol. Concentrate in vacuo, then use a method similar to the GeneralProcedure 2-1 and freeze dry to give the title compound as a solid (150mg, 69%). MS (ES+) m/z: 347 (M+H)⁺.

EXAMPLE 6617-Chloro-6-(3-methylcarbamoyl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

3-tert-Butoxycarbonyl-7-chloro-6-(3-carboxy-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add potassium hydroxide (700 mg, 12.5 mmol) in one portion to a solutionof3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(150 mg, 0.39 mmol) in methanol (10 mL). Heat the reaction at refluxunder nitrogen 4 h. Then cool to room temperature, add 4-bromo-butyricacid (65 mg, 0.39 mmol) and stir for 3 days. Remove solvents in vacuo,neutralize with ammonium chloride (200 mL) and extract into EtOAc (2×50mL). Dry over MgSO₄, filtrate and concentrate in vacuo to give a clearoil (125 mg). Dissolve the oil in anhydrous DMF (10 mL) and add sodiumhydride (30 mg, 0.78 mmol of 60% dispersion in oil) under nitrogen. Stirfor 30 min. Add 4-bromo-butyric acid (65 mg, 0.39 mmol) and stir for 30min. Pour into water (50 mL) and extract with diethyl ether (2×50 mL).Wash the combined organic extracts with brine (50 mL) and dry overMgSO₄. Concentrate the filtrate in vacuo to give the desiredintermediate as a solid (146 mg, 94%). MS (ES+) m/z: 398 (M+H)⁺.3-tert-Butoxycarbonyl-7-chloro-6-(3-methylcarbamoyl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(123 mg, 0383 mmol) portion wise to a solution of3-tert-butoxycarbonyl-7-chloro-6-(3-carboxy-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(146 mg, 0365 mmol) and methylamine (182 μL, 0.365 mmol) in anhydrousDMF (5 mL) under nitrogen at 0° C. Stir for 15 min then adddiisopropylethylamine (127 μL, 0.73 mmol) in anhydrous DMF (1 mL) andcontinue to stir at, 0° C. for 1 h. Warm to room temperature andcontinue to stir overnight Pour into water (50 mL) and extract withEtOAc (3×20 mL). Wash the combined organic extracts with saturatedaqueous NaHCO₃ (50 mL) and brine (50 mL). Dry over MgSO₄, filtrate andconcentrate in vacuo to give a pale yellow oil (74 mg). MS (ES+) m/z:398 (M+H)⁺. Purify using Mass-guided reverse phase HPLC [SupelcoDiscovery C18 column (21.2×100 mm, 5 μm packing), 25 mL/min flow rate,eluting with water/acetonitrile/acetic acid gradient over 12 min,fraction collection triggered by Electrospray MS]. Concentrate in vacuoto give the desired intermediate as a colourless oil (30 mg, 20%). MS(ES+) m/z: 435 (M+Na)⁺.7-Chloro-6-(3-methylcarbamoyl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate: Dissolve3-tert-butoxycarbonyl-7-chloro-6-(3-methylcarbamoyl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(30 mg, 0.07 mmol) in dichloromethane (10 mL) then add TFA (0.5 mL)dropwise and stir at room temperature for 3 days. Remove solvents invacuo then free base using an SCX column, eluting with 7M ammonia inmethanol. Concentrate in vacuo, then use a method similar to the GeneralProcedure 2-1 and freeze dry to give the title compound as a solid (21mg, 72%). MS (ES+) m/z: 313 (M+H)⁺.

EXAMPLE 6627-Chloro-6-(1-cyano-1-methyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

3-tert-Butoxycarbonyl-7-chloro-6-(1-cyano-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Add potassium hydroxide (10.8 g, 192 mmol) to a solution of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(3 g, 7.8 mmol) in degassed methanol (150 mL) under a nitrogenatmosphere. Heat the mixture at 80° C. for 6 h. Cool the mixture toambient temperature, then concentrate in vacuo to an oil. Dissolve theoil in EtOAc (50 mL), wash with aqueous saturated ammonium chloride (30mL). Separate the organic layer and extract the aqueous layer with EtOAc(3×50 mL). Dry the combined organic extracts over Na₂SO₄, filter andconcentrate in vacuo to an oil (2.4 g). Dissolve the oil in anhydrous Do(50 mL). Slowly add sodium hydride (470 mg, 11.7 mmol) portionwise over5 min followed by 2-bromopropionitrile (1 mL, 11.7 mmol). Stir themixture under nitrogen at ambient temperature for 16 h. Dilute themixture slowly with EtOAc (100 mL) and wash with cold aqueous saturatedammonium chloride (50 mL). Separate the organic layer and extract theaqueous-layer with EtOAc (3×50 mL). Combine the organic extracts andconcentrate in vacuo. Purify the crude mixture by chromatography onsilica gel eluting with hexane/EtOAc (19:1 to 3:1 gradient) to obtainthe desired intermediate (2.5 g, 89%). MS (ES+) m/z: 267.2 (M-Boc)⁺.3-tert-Butoxycarbonyl-7-chloro-6-(1-cyano-1-methyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine:Slowly add a solution of3-tert-butoxycarbonyl-7-chloro-6-(1-cyano-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(2.5 g, 6.8 mmol) in anhydrous THF (20 mL) to a slurry of sodium hydride(1.4 g, 34 mmol) in anhydrous THF (50 mL) at 0° C. under a nitrogenatmosphere. Stir the slurry for 5 min, then add iodomethane (12.7 mL,204 mmol) to the slurry while maintaining the temperature below 30° C.Stir the mixture for 3 h at ambient temperature then quench withmethanol (10 mL) and concentrate in vacuo. Purify the crude mixture bychromatography on silica gel eluting with hexane/EtOAc (19:1 to 9:1gradient) to obtain the desired intermediate (2 g, 79%). MS (ES+) m/z:281.2 (M+H-Boc)⁺.7-Chloro-6-(1-cyano-1-methyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate: Use a method similar to the General Procedure 1-5 todeprotect3-tert-butoxycarbonyl-7-chloro-6-(1-cyano-1-methyl-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.4 g, 3.5 mmol). Purify by chromatography on silica gel eluting withdichloromethane/2M ammonia in methanol (99:1 to 90:10 gradient) to givethe free base of the title compound. Use a method similar to the GeneralProcedure 2-1 to obtain the title compound (992 mg, 71%). MS (ES+) m/z:281.2 (M+H)⁺.

EXAMPLE 6637-Chloro-6-(1-cyano-cyclopropylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Add potassium hydroxide (5.4 g, 96.2 mmol) to a solution of3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.5 g, 4.7 mmol) in degassed methanol (75 mL) under a nitrogenatmosphere. Heat the mixture at 80° C. for 6 h Cool the mixture toambient temperature, then concentrate in vacuo to an oil. Dissolve theoil in EtOAc (50 mL) and wash with saturated aqueous ammonium chloride(30 mL). Separate the organic layer and extract the aqueous layer withEtOAc (3×50 mL). Dry the combined organic extracts over Na₂SO₄, filterand concentrate in vacuo to an oil (1.4 g). Dissolve the oil inanhydrous DMF (25 mL), then slowly add sodium hydride (282 mg, 7.1 mmol)and bromoacetonitrile (470 μl, 7.1 mmol). Stir the mixture undernitrogen at ambient temperature for 16 h. Dilute the mixture slowly withEtOAc (100 mL) and wash with cold aqueous saturated ammonium chloride(40 mL). Separate the organic layer and extract the aqueous layer withEtOAc (3×50 mL). Combine the organic extracts and concentrate in vacuo.Purify the residue by chromatography on silica gel eluting withhexane/EtOAc (9:1 to 7:3 gradient) to obtain3-tert-butoxycarbonyl-7-chloro-6-(1-cyano-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(1.34 g, 81%). MS (ES+) m/z: 253.2 (M-Boc)⁺.

Add sodium bis(trimethylsilyl)amide (5.4 mL, 5.4 mmol, 1M solution inTHF) at room temperature under nitrogen to a solution of3-tert-butoxycarbonyl-7-chloro-6-(1-cyano-methylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(380 mg, 1.1 mmol) in anhydrous toluene (4 mL). Stir the solution for 10min, then add quickly 1,2-dibromoethane (2.8 mL, 32.4 mmol) followed byanhydrous DMF (4 mL). An exothermic reaction was observed and thereaction temperature increased to 38° C. Stir the mixture for 15 min atambient temperature, then quench with methanol (2 mL). Concentrate invacuo and purify by chromatography on silica gel eluting withhexane/EtOAc (9:1) to obtain3-tert-butoxycarbonyl-7-chloro-6-(1-cyano-cyclopropylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(259 mg).

Use a method similar to the General Procedure 1-5 to deprotect3-tert-butoxycarbonyl-7-chloro-6-(1-cyano-cyclopropylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.Purify by reverse phase chromatography [Column: Symmetry C18, 19×300 mm,flow rate 30 mL/min, eluting with water with 0.1% TFA/acetonitrile (19:1to 1:1 gradient)] followed by SCX chromatography to obtain the free baseof the title compound. Use a method similar to the General Procedure 2-1to obtain the title compound (120 mg, 28% yield over 3 steps). MS (ES+)m/z: 279.2 (M+H)⁺.

EXAMPLE 6646-(4-tert-Butylcarbamoyl-benzylthio)-7-chloro-9-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to Example 456 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-9-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith 4-chloromethyl-N-(tert-butyl)-benzamide.

Use methods similar to the General Procedures 1-5 and 2-1 to give thetitle compound as a white solid. MS (ES+) m/z: 421 (M+H)⁺.

EXAMPLE 6657-Chloro-6-[4-(3,3-dimethylbutyryl)-benzylthio]-9-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate

Use a method similar to Example 435 to react3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-9-fluoro-2,3,4,5-tetrahydro-1H-benzo[d]azepinewith 1-(4-bromomethylphenyl)-3,3-dimethylbutan-1-one.

Use methods similar to the General Procedures 1-5 and 2-2 to give thetitle compound as a white solid. MS (ES+) m/z: 420 (M+H)⁺.

Preparation 346 4-(2,2-Dimethyl-propane-1-sulfonyl)-

1-(2,2-Dimethyl-propylthio)-4-methyl-benzene: Dissolve4-methyl-benzenethiol (1.5 g, 12.08 mmol) in anhydrous DMF (6 mL). Coolthe solution to 0° C., add sodium hydride (435 mg, 17.21 mmol, 95%) andstir the mixture under nitrogen atmosphere for 15 mm. Add1-iodo-2,2-dimethylpropane (1.93 mL, 14.5 mmol), stir the mixture for 1h at 0° C., warm to room temperature and stir overnight. Add water andextract the aqueous phase twice with EtOAc. Wash the combined organicextracts twice with iced-water, dry over Na₂SO₄, filter and concentratein vacuo to give the desired intermediate (1.476 g, 63% yield).1-(2,2-Dimethyl-propane-1-sulfonyl)-4-methyl-benzene: Dissolve1-(2,2-dimethyl-propylthio)-4-methyl-benzene (1.476 g, 7.6 mmol) intrifluoroacetic acid (9.5 mL). Add dropwise hydrogen peroxide (9.9 mL,30% in water), cool the mixture to 0° C. and stir 15 min at thistemperature and 45 min at room temperature. Concentrate the mixture invacuo, dilute with saturated aqueous NaHCO₃ and extract the aqueousphase twice with EtOAc. Dry the combined organic extracts over Na₂SO₄,filter and concentrate in vacuo to give the desired intermediate (1.548g, 90%).1-Bromomethyl-4-(2,2-dimethyl-propane-1-sulfonyl)-benzene: Use a methodsimilar to the Preparation 213 (Step 2), using1-(2,2-dimethyl-propane-1-sulfonyl)-4-methyl-benzene (560 mg, 2.47 mmol)to give the desired intermediate.N-(di-tert-Butoxycarbonyl)-4-(2,2-dimethyl-propane-1-sulfonyl)-benzylamine:Add sodium hydride (60 mg; 2.39 mmol) to a solution ofdi-tert-butyl-iminodicarboxylate (519 mg, 2.39 mmol) in anhydrous DMF (2mL) at room temperature under nitrogen and stir for 15 min. Then add asolution of 1-bromomethyl-4-(2,2-dimethyl-propane-1-sulfonyl)-benzene(731 mg, 2.39 mmol) in anhydrous DMF (3 mL) and stir for 1.5 h. Addwater and extract the aqueous phase twice with EtOAc. Wash the combinedorganic extracts with iced-water. Dry the organic layer over Na₂SO₄,filter and concentrate in vacuo. Purify by chromatography on silica geleluting with hexane/EtOAc (88:12) to obtain the desired intermediate(460 mg, 44% over 2 steps).4-(2,2-Dimethyl-propane-1-sulfonyl)-benzylamine: Add 4N hydrogenchloride in dioxane (2 mL) to a solution ofN-(di-tert-butoxycarbonyl)-4-(2,2-dimethyl-propane-1-sulfonyl)-benzylamine(460 mg, 1.04 mmol) in dichloromethane (20 mL) and stir overnight.Concentrate in vacuo, suspend the solid obtained in EtOAc, add saturatedaqueous NaHCO₃ and stir until both phases are clear. Extract the aqueousphase three times with dichloromethane EtOAc. Dry the combined organicextracts over Na₂SO₄, filter and concentrate in vacuo to obtain thetitle compound as an oil that was used without any further purification(166 mg, 71% yield). MS (ES+) m/z: 242 (M+H)⁺.

The compounds of Preparations 347-348 may be prepared essentially asdescribed in Preparation 346 using 1-iodo-3,3,3-trifluoropropane(Preparation 347) or 1,1,1-trifluoro-3-iodobutane (Preparation 348). MS(ES+) data are shown in the Table below.

MS (ES+) Prep. Structure Compound m/z 347

4-(3,3,3-Trifluoro-propane-1-sulfonyl)-benzylamine 268(M + H)⁺ 348

4-(4,4,4-Trifluoro-butane-2-sulfonyl)-benzylamine 282(M + H)⁺

Preparation 349 4-(2-Methyl-propane-2-sulfonylmethyl)-benzylamine

4-tert-Butylthiomethyl-benzonitrile: Add sodium hydride (359 mg, 14.21mmol) to a solution of 2-methyl-2-propanethiol (900 mg, 9.98 mmol) inanhydrous DMF (15 mL) under nitrogen. Stir the mixture for 15 min, add4-bromomethyl-benzonitrile (2.348 g, 11.97 mmol) and stir the resultingmixture overnight at room temperature. Add water and extract the aqueousphase twice with EtOAc. Wash the combined organic extracts twice withiced-water, dry over Na₂SO₄, filter and concentrate in vacuo. Purify bychromatography on silica gel eluting with hexane/EtOAc 92:8 to give thedesired intermediate (1.42 g, 69% yield).4-(2-Methyl-propane-2-sulfonylmethyl)-benzonitrile: Dissolve4-tert-butylthiomethyl-benzonitrile (1.42 g, 6.9 mmol) intrifluoroacetic acid (9 mL). Add dropwise hydrogen peroxide (9 mL, 30%in water), cool the mixture to 0° C. and stir 15 min at this temperatureand 45 min at room temperature. Concentrate the mixture in vacuo, dilutewith saturated aqueous NaHCO₃ and extract the aqueous phase twice withEtOAc. Dry the combined organic extracts over Na₂SO₄, filter andconcentrate in vacuo to give the desired intermediate (1.46 g, 89%).4-(2-Methyl-propane-2-sulfonylmethyl)-benzylamine: Dissolve4-(2-methyl-propane-2-sulfonylmethyl)-benzonitrile (300 mg, 1.26 mmol)in methanol (50 mL). Add concentrated HCl (10 drops), 10% Pd/C (Degussatype E101, 60 mg) and submit the mixture to hydrogenation at atmosphericpressure for 1 h. Filter over Celite® and wash with methanol.Concentrate the filtrate in vacuo to give the hydrochloride salt of thetitle compound as a solid that was washed with diethyl ether (366 mg,87%). Partition the solid between saturated NaHCO₃ and EtOAc and extractthe aqueous phase twice with EtOAc. Dry the combined organic extractsover Na₂SO₄, filter and concentrate in vacuo to give the title compound(195 mg, 74%). MS (ES+) m/z: 242 (M+H)⁺.

The compound of Preparation 350 may be prepared essentially as describedin Preparation 349 using 4-(2-bromo-ethyl)-benzonitrile. MS (ES+) dataare shown in the Table below.

MS (ES+) Prep. Structure Compound m/z 350

4-[2-(2-Methyl-propane-2-sulfonyl)-ethyl]-benzylamine 256(M + H)⁺

Preparation 351 3-Aminomethyl-6-(2-cyclohexyl-ethyl)-pyridine

6-Cyclohexylethynyl-nicotinonitrile: Add cyclohexylacetylene (1.54 mL,11.6 mmol), dichlorobis(triphenylphosphine)palladium (200 mg, 0.28mmol), copper iodide (100 mg, 0.53 mmol), and triethylamine (2.0 mL,14.3 mmol) to a solution of 6-chloronicotinonitrile (1.38 g, 9.9 mmol)in DMF (4 mL). Heat the mixture in a sealed flask for 3 h at 100° C.Cool the mixture to room temperature, dilute with 1:1 hexane/EtOAc (100mL) and wash with an aqueous 10% sodium chloride solution (3×30 mL).Collect the organic layer, concentrate in vacuo, and purify the residueby silica gel chromatography (90 g silica, hexane/EtOAc 95/5 to 85/15gradient) to obtain the desired intermediate (1.75 g, 83%)3-tert-Butoxycarbonyl-aminomethyl-6-(2-cyclohexyl-ethyl)-pyridine: Add6-cyclohexylethynyl-nicotinonitrile (1.75 g, 8.3 mmol), 10% Pd/c(Degussa type E101, 50% water by wt) (1.0 g), methanol (100 mL), anddi-t-butyl dicarbonate (2.3 g, 10.4 mmol) to a pressure vessel under anitrogen atmosphere. Pressurize the vessel to 30 psi with hydrogen, andstir the mixture for 3 h (monitor the reaction by TLC). Purge the vesselwith nitrogen, filter the mixture through Celite® and wash the cake withdichloromethane under a nitrogen atmosphere. Concentrate the filtrate invacuo. Purify the residue by silica gel chromatography (90 g silica,hexane/EtOAc, 95/5 to 50/50 gradient) to obtain the desired intermediate(1.05 mg, 40%). MS (ES+) m/z: 319.2 (M+H)⁺.3-Aminomethyl-6-(2-cyclohexyl-ethyl)-pyridine: Add trifluoroacetic acid(2.0 mL) to a solution of3-tert-butoxycarbonyl-aminomethyl-6-(2-cyclohexyl-ethyl)-pyridine (1.05g, 3.3 mmol) in methanol (20 mL). Stir the solution for 1 h at roomtemperature under a nitrogen atmosphere. Concentrate the solution invacuo and purify the residue via SCX chromatography to obtain thedesired intermediate (670 mg, 93%). MS (ES+) m/z: 219.2 (M+H)⁺.

Preparation 352 2-Aminomethyl-5-(2-cyclohexyl-ethyl)-pyridine

The title compound may be prepared essentially as described inPreparation 351 by using 5-chloro-pyridine-2-carbonitrile (24% yield, MS(ES) m/z 219.2 (M+H)⁺.

EXAMPLE 6667-Chloro-6-[4-(2,2-dimethyl-propane-1-sulfonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate

Use a method similar to the General Procedure 5-2 to couple7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine(158 mg, 0.37 mmol) with 4-(2,2-dimethyl-propane-1-sulfonyl)-benzylamine(166 mg, 0.73 mmol) by using tris(dibenzylideneacetone)dipalladium(0)(68 mg, 0.074 mmol), BINAP (92 mg, 0.148 mmol) and cesium carbonate (169mg, 0.518 mmol) in anhydrous toluene (15 mL). Purify by chromatographyon silica gel eluting with hexane/EtOAc (8:2) and then by reversed HPLC[Zorbax Bonus RP, 5 □M 21.2×100 mm, eluting with water/acetonitrile(0.05% TFA in each), UV detector (230 nm)] to give7-chloro-6-[4-(2,2-dimethyl-propane-1-sulfonyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineas an oil (153 mg, 80%). MS (ES+) m/z: 517 (M+H)⁺.

Use methods similar to the General Procedures 1-2 and 2-6 to give thetitle compound as a white solid. MS (ES+) m/z: 421 (M+H)⁺.

Examples 667-672 may be prepared essentially as described in Example 666using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Examples 673-674 may be prepared essentiallyas described in Example 666 using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine but the succinate salt was prepared asdescribed in General Procedure 2-1. MS (ES+) data are shown in the Tablebelow.

MS Ex. Structure Compound (ES+) m/z 667

7-Chloro-6-[4-(4,4,4-trifluorobutane-2-sulfonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate461(M + H)⁺ 668

7-Chloro-6-[4-(2-methyl-propane-2-sulfonylmethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate421(M + H)⁺ 669

7-Chloro-6-[4-(2-methyl-propane-2-sulfonylethyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate435(M + H)⁺ 670

7-Chloro-6-[4-(4,4-dimethyl-3-oxo-pentyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 399(M + H)⁺ 671

7-Chloro-6-[4-(t-butylthiomethyl-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 389(M + H)⁺ 672

7-Chloro-6-[4-(t-butylthioethyl-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate403(M + H)⁺ 673

7-Chloro-6-[(6-cycloheptylthio-pyridin-3-ylmethyl)-amino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 416(M + H)⁺ 674

7-Chloro-6-[4-(3,3,3-trifluoropropane-1-sulfonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate447(M + H)⁺

Examples 675-676 may be prepared essentially as described in Example 604using7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine but the (L)-tartrate salt was prepared asdescribed in General Procedure 2-6. MS (ES+) data are shown in the Tablebelow.

MS (ES+) Ex. Structure Compound m/z 675

7-Chloro-6-(5-cyclohexylethyl-pyridin-2-yl-methylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 398(M + H)⁺ 676

7-Chloro-6-(6-cyclohexylethyl-pyridin-3-yl-methylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine(L)-Tartrate 398(M + H)⁺

Examples 677-684 may be prepared essentially as described in Example 563by using3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. Examples 685-689 may be prepared essentiallyas described in Example 563 by using3-tert-butoxycarbonyl-6-(4-carboxy-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepineand the appropriate amine. MS (ES+) data are shown in the Table below.

MS (ES+) Ex. Structure Compound m/z 677

7-Chloro-6-[4-(2,2,2-trifluoroethylcarbamoyl)-3-fluoro-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 430(M + H)⁺ 678

7-Chloro-6-[4-(2-butylcarbamoyl)-3-fluoro-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 404(M + H)⁺ 679

7-Chloro-6-[4-(2-cycloheptylcarbamoyl)-3-fluoro-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 458(M + H)⁺ 680

7-Chloro-6-[4-(4-heptylcarbamoyl)-3-fluoro-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 446(M + H)⁺ 681

7-Chloro-6-[4-(3-pentylcarbamoyl)-3-fluoro-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 418(M + H)⁺ 682

7-Chloro-6-[4-(4-methyl-2-pentylcarbamoyl)-3-fluoro-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 432(M + H)⁺ 683

7-Chloro-6-[4-(3-methyl-2-butylcarbamoyl)-3-fluoro-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 418(M + H)⁺ 684

7-Chloro-6-[4-(ethylcarbamoyl)-3-fluoro-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 376(M + H)⁺ 685

7-Chloro-6-[4-(2-cycloheptylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 440(M + H)⁺ 686

7-Chloro-6-[4-(4-heptylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 428(M + H)⁺ 687

7-Chloro-6-[4-(3-pentylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 400(M + H)⁺ 688

7-Chloro-6-[4-(4-methyl-2-pentylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 414(M + H)⁺ 689

7-Chloro-6-[4-(3-methyl-2-butylcarbamoyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepineSuccinate 400(M + H)⁺

The compounds of the present invention are relatively selective for the5-HT_(2C) receptor. The compounds of the present invention areparticularly relatively selective for the 5-HT_(2C) receptor incomparison to other 5-HT receptor subtypes and specifically the

5-HT_(2A) and 5-HT_(2B) receptors. This selectivity is demonstrated inthe following agonist activity assays and receptor binding assays.

Agonist Activity Assays (G alpha q-GTPγ[³⁵S] Binding Assays)

The 5-HT₂ receptors are functionally coupled to specific G-proteins.Agonist activation of 5-HT₂ G-protein-coupled receptors results in therelease of GDP from the α-subunit (G alpha q or G alpha i) of theG-protein and the subsequent binding of GTP. The binding of the stableanalog GTPγ[³⁵S] is an indicator of receptor activation (i.e. agonistactivity).

The G alpha q-GTPγ[³⁵S] binding assay is used to determine the in vitropotency (EC₅₀) and maximal efficacy (E_(max), normalized to the 5-HTresponse) of a test compound at the 5-HT_(2A), 5-HT_(2B), and 5-HT_(2C)receptors. The area under the dose response curve (AUC) is alsodetermined for each receptor subtype and used to measure the testcompound's selectivity for the 5-HT_(2C) receptor over the 5-HT_(2A) and5-HT_(2B) receptors, expressed as Selectivity Ratios (AUC 2C/2A and AUC2C/2B, respectively). The Selectivity Ratios allow the assessment ofselectivity based on both potency and efficacy. A selectivity measurethat incorporates both potency and efficacy at the 5-HT_(2C) receptor,as compared to the 5-HT_(2A) and 5-HT_(2B) receptors, is consideredimportant due to the adverse events associated with 5-HT_(2A) and5-HT_(2B) agonist activity (see introduction).

Membrane Preparation: Grow AV12 cells stably transfected with the human5-HT_(2A), 5-HT_(2B), or 5-HT_(2C) receptors in suspension, harvest bycentrifugation, wash the cell pellet with phosphate buffered saline, pH7.4, pellet the cells again, remove the supernatant, freeze the cellpellet on dry ice and store at −70° C. Thaw stock cell pellet andresuspend in 50 mM Tris, pH 7.4, aliquot into 1-2 mL volumes andrefreeze at −70° C. for subsequent assays. (As is appreciated in theart, optimal cell quantities used per aliquot will vary with theindividual transfected cell line used. In one embodiment, 5-HT_(2A) and5-HT_(2C) transfected cells are typically used at about 6×10⁸ cells peraliquot, while 5-HT_(2B) cells are typically used at about 7.5×10⁸ cellsper aliquot).

On the day of assay, thaw membranes, wash the membranes with assaybuffer (50 mM Tris-HCl (pH 7.4), 10 mM MgCl₂, 100 mM NaCl, and 0.2 mMEDTA), resuspend in assay buffer and incubate for 10 min. at 37° C. tohydrolyze any residual endogenous 5-HT. Wash the membranes again withassay buffer, and resuspend in assay buffer at a concentration toprovide aliquots of about 1-4×10⁶ cell equivalents per well (typicallyabout 1-2×10⁶ cell equivalents for assays with 5-HT_(2A) or 5-HT_(2C)receptor assays, and about 3-4×10⁶ cell equivalents for assays with5-HT_(2B) receptor assays). Homogenize the cells with a tissue grinderand use the homogenate directly in the assay as described below.

G alpha q-GTPγ[³⁵S] Binding Assays: The immunoadsorption scintillationproximity assay (ISPA) of [³⁵S]-GTPγS binding to G alpha q is modifiedfrom published conditions (DeLapp et al, JPET 289 (1999) 946-955).Dissolve test compounds in DMSO and dilute in assay buffer to provide arange of concentrations to generate a concentration response curve. Inwells of a 96 well microtiter plate, mix diluted test compound, GDP (0.1μM final concentration), and [³⁵S]-GTPγS (between 0.5 and 1.0 nM finalconcentration). Add an aliquot of membranes to the incubation mixtureand mix the plates to initiate agonist stimulation of the nucleotideexchange (200 μl final volume). Incubate the microtiter plates for 30min. at room temperature. Quench the incubation with IGEPAL® CA-630detergent (0.27% final concentration). Add affinity purified polyclonalrabbit anti-G alpha q antibody (about 1-2 μg per well), and anti-rabbitIg scintillation proximity assay beads (Amersham; about 1.25 mg perwell; 300 μl final volume). Seal the plates and incubate the mixture for3 h at room temperature. Centrifuge the microtiter plates briefly topellet beads. Quantitate the GTPγ[³⁵S] binding by microtiter platescintillation spectrometry (Wallac Trilux MicroBeta™ scintillationcounter).

Data Analysis: For each concentration response curve for a test compoundat a given receptor, analyze the data with GraphPad Prism™ software(v3.O2; GraphPad Software, San Diego, Calif.) running on a personalcomputer with Micro Soft Windows OS®, using nonlinear regressionanalysis curve fitting to determine the EC₅₀ and E_(max) (normalized to5-HT control curves). Determine the Area Under the agonistconcentration-response Curve (AUC) with GraphPad Prism™ by thetrapezoidal method.

To calculate the Selectivity Ratios, first, determine the AUC for thetest compound for each receptor subtype as described above. Second,normalize the AUC's at each receptor subtype relative to the AUCdetermined for 5-HT at that receptor. The normalized AUC for a testcompound at a given receptor is therefore expressed as a percentage ofthe AUC determined for 5-HT at that receptor. For example:

${5\; {HT}_{2A}\mspace{11mu} {Normalized}\mspace{14mu} A\; U\; C} = {a = {\frac{\begin{pmatrix}{A\; U\; C_{{test}\mspace{14mu} {compound}}\mspace{14mu} {at}} \\{5\; {HT}_{2A}\mspace{14mu} {receptor}}\end{pmatrix}}{\begin{pmatrix}{A\; U\; C_{5\text{-}{HT}}\mspace{14mu} {at}} \\{5\; {HT}_{2A}\mspace{14mu} {receptor}}\end{pmatrix}} \times 100\%}}$${5\; {HT}_{2B}\mspace{11mu} {Normalized}\mspace{14mu} A\; U\; C} = {b = {\frac{\begin{pmatrix}{A\; U\; C_{{test}\mspace{14mu} {compound}}\mspace{14mu} {at}} \\{5\; {HT}_{2B}\mspace{14mu} {receptor}}\end{pmatrix}}{\begin{pmatrix}{A\; U\; C_{5\text{-}{HT}}\mspace{14mu} {at}} \\{5\; {HT}_{2B}\mspace{14mu} {receptor}}\end{pmatrix}} \times 100\%}}$${5\; {HT}_{2C}\mspace{11mu} {Normalized}\mspace{14mu} A\; U\; C} = {c = {\frac{\begin{pmatrix}{A\; U\; C_{{test}\mspace{14mu} {compound}}\mspace{14mu} {at}} \\{5\; {HT}_{2C}\mspace{14mu} {receptor}}\end{pmatrix}}{\begin{pmatrix}{A\; U\; C_{5\text{-}{HT}}\mspace{14mu} {at}} \\{5\; {HT}_{2C}\mspace{14mu} {receptor}}\end{pmatrix}} \times 100\%}}$

Third, calculate the Selectivity Ratios for the test compound asfollows:

Selectivity Ratio for 5-HT_(2C) receptor/5-HT_(2A) receptor (AUC2C/2A)=c/a

Selectivity Ratio for 5-HT_(2C) receptor/5-HT_(2B) receptor (AUC2C/2B)=c/b

For reference purposes, the AUC 2C/2A and AUC 2C/2B for 5-HT are each1.0. Likewise, the ratios for mCPP (meta-chlorophenylpiperazine) aretested and are found to be 2.1 and 2.1 respectively.

Representative compounds of the present invention are tested in the Galpha q-GTPγ[³⁵S] assays for the 5-HT_(2A), 5-HT_(2B), and 5-HT_(2C)receptors essentially as described above and are found to be a highlypotent and selective agonists of the 5-HT_(2C) receptor, with EC₅₀'stypically less than or equal to 200 nM, and AUC 2C/2A and AUC 2C/2Bratios greater than 1.5. Preferred compounds are those with EC50's lessthan or equal to 100 nM, and AUC 2C/2A and AUC 2C/2B ratios greater thanor equal to 2.0. More preferred are those with EC50's less than or equalto 50 nM, and AUC 2C/2A and AUC 2C/2B ratios greater than or equal to3.0.

Ligand Binding Assays

The ligand binding affinity of the compounds of the present invention tothe 5-HT_(2C) receptor subtype is measured essentially as described byWainscott (Wainscott, et al., Journal of Pharmacology and ExperimentalTherapeutics, 276:720-727 (1996)). Data is analyzed by nonlinearregression analysis on the concentration response curves using the fourparameter logistic equation described by DeLean (DeLean, et al.,Molecular Pharmacology, 21, 5-16 (1982)). IC₅₀ values are converted toK_(i) values using the Cheng-Prusoff equation (Cheng, et al., Biochem.Pharmacol., 22, 3099-3108 (1973)).

Representative compounds of the present invention are tested essentiallyas described above and are found to have excellent affinity for the5-HT_(2C) receptor, with K_(i)'s typically less than or equal to about200 nM. Preferred compounds are those with K_(i)'s of less than or equalto about 100 nM. More preferred are those with K_(i)'s less than orequal to 50 nM.

Affinities for other receptor subtypes can readily be determined byslight modification of the above described radioligand receptor bindingassay using cells transfected with the desired receptor in place ofcells transfected with the 5-HT_(2C) receptor subtype and using anappropriate radioligand. The binding affinities for representativecompounds of the present invention for a variety of receptors aredetermined in such assays and the compounds are found to havesurprisingly higher affinity for the 5-HT_(2C) receptor. Affinity forthe 5-HT_(2C) receptor is found to be significantly higher than forother 5-HT receptor subtypes, and notably higher than the 5-HT_(2A) and5-HT_(2B) receptor subtypes. Preferred compounds are those with IC₅₀'sequal to or greater than 300 nM for the alpha 1 and alpha 2 adrenergicreceptors and equal to or greater than 500 nM for D₁ and D₂ dopaminergicreceptors. More preferred compounds are those with IC₅₀'s equal to orgreater than 1000 nM for the alpha 1 and alpha 2 adrenergic receptorsand the D₁ and D₂ dopaminergic receptors. Still more preferred are thosecompounds with IC₅₀'s equal to or greater than 3000 nM for the alpha 1and alpha 2 adrenergic receptors and the D₁ and D₂ dopaminergicreceptors.

For the above in vitro assays, exemplified compounds are assayed andfound to have either an EC₅₀ or a K; value of equal to or less than 50nM, and to have AUC 2C/2A and AUC 2C/2B ratios of greater than or equalto 2.0. Exemplified compounds are assayed and found to have alpha 1 andalpha 2 adrenergic receptor IC₅₀'s equal to or greater than 300 nM, andD₁ and D₂ dopaminergic receptor IC₅₀'s equal to or greater than 500 nM.

Rat Feeding Assays

The ability of the compounds of the present invention to treat obesityis demonstrated by testing in acute and chronic rat feeding assays.

Animals: Obtain male Long-Evans rats (Harlan Sprague-Dawley,Indianapolis, Ind.) that are approximately one hundred-days old and havebeen maintained on a calorie rich diet since weaning (TD 95217, 40%calories from fat; Teklad, Madison, Wis.). House the rats individuallywith a 12 h:12 h light:dark cycle (lights on from about 22:00 h to about10:00 h) and maintain rats on the same diet (TD 95217) with free accessto water, for about 1-2 weeks to acclimate the rats to the environment.Dose rats orally with vehicle (10% acacia with 0.15% saccharin in water)once daily for at least 1 day (typically 1-2 days) to acclimate the ratsto the procedures. Randomize the rats into groups so each group hassimilar mean body weights.Calorimetric Acute Feeding Assay: At approximately 8:00 h on the day ofassay, weigh each rat and transfer to individual chambers of an opencircuit calorimetry system (Oxymax, Columbus Instruments InternationalCorporation; Columbus, Ohio), with free access to food (pre-weighed) andwater, and begin measuring VO₂ and VCO₂. At approximately 10:00 h, doserats orally with vehicle or test compound, return them to theircalorimetry chambers, and continue measuring VO₂ and VCO₂ at regulartime intervals (approximately hourly). At approximately 8:00 h thefollowing day, measure rat body weight and the remaining food, assumingthe difference in weight of food is equal to the mass of food consumed.Calculate the 24 h energy expenditure (EE) and respiratory quotient (RQ)essentially as described in Chen, Y. and Heiman, M. L., RegulatoryPeptide, 92:113-119 (2000). EE during light photoperiod is indicative ofthe resting metabolic rate and RQ is indicative of the fuel source theanimal utilizes (pure carbohydrate metabolism gives an RQ of about 1.0,pure fat metabolism gives an RQ of about 0.7, mixed carbohydrate and fatmetabolism gives intermediate values for RQ). Calculate EE as theproduct of calorific value (CV) and VO₂ per body weight (kg); whereCV=3.815+1.232*RQ, and RQ is the ratio of CO₂ produced (VCO₂) to O₂consumed (VO₂). Caloric intake is calculated as (mass of 24 h foodintake in grams)×(physiological fuel value of the diet in kilocalorie/g)per kg of body weight.Acute Feeding Assay with a selective 5-HT_(2C) receptor antagonist: Theabove calorimetric acute feeding assay is conducted with the followingmodifications. Open circuit calorimetry systems are not used and onlythe 24 h periodic food intake and body weight are measured. Three groupsof rats are used with the first group receiving a subcutaneous dose ofsaline (0.5 mL) about 15 minutes prior to the oral dose of vehicle, thesecond group receiving a subcutaneous dose of saline (0.5 mL) about 15minutes prior to the oral dose of test compound in vehicle, and thethird group receiving a subcutaneous injection of a selective 5-HT_(2C)receptor antagonist,6-chloro-5-methyl-N-{2-[(2-methylpyridin-3-yl-oxy)pyridin-5-yl]aminocarbonyl}-2,3-dihydroindole(3 mg/Kg, in 35% cyclodextrin, 0.5 mL), about 15 min. prior to the oraldose of test compound in vehicle.Chronic Feeding Assay: At between approximately 8:00 h and 10:00 h onday one of the assay, weigh and orally dose each rat with vehicle ortest compound and return the animal to its home cage, with free accessto food (pre-weighed) and water. For each of days 2-15, at betweenapproximately 8:00 h and 10:00 h, measure rat body weight and the weightof food consumed in the last 24 h period, and administer daily oral doseof test compound or vehicle. On days −2 and 15 measure total fat massand lean mass by nuclear magnetic resonance (NMR) using an EchoMRI™system (Echo Medical Systems, Houston Tex.). (See Frank C. Tinsley,Gersh Z. Taicher, and Mark L. Heiman, “Evaluation of a New QuantitativeMagnetic Resonance (QMR) Method for Mouse Whole Body CompositionAnalysis”, Obesity Research, submitted May 1, 2003.)

Representative compounds of the present invention are tested in acuteand chronic feeding assays essentially as described above. In the acuteassays, the compounds are found to significantly reduce 24 h foodintake, which effect is blocked by pre-administration of the 5-HT_(2C)receptor antagonist. The compounds also are found to dose-dependentlyreduce RQ without significantly changing the energy expenditure duringthe light photo-period. Thus the compounds are found to reduce caloricintake and increase the proportion of fuel deriving from fatutilization, without significantly changing the resting metabolic rate.In the chronic assay, the compounds are found to significantly decreasecumulative food intake and cumulative body weight change in adose-dependent manner compared to control animals. The decrease in bodyweight is found to be due to loss of adipose tissue while lean body massis not changed.

The ability of the 5-HT_(2C) receptor agonists of the present inventionto treat obsessive/compulsive disorder is demonstrated by testing in avariety of in vivo assays as follows:

Marble Burying Assay

Marble burying in mice has been used to model anxiety disordersincluding obsessive-compulsive disorders (OCD) due to ethological studyof the behavior (e.g. Gyertyan I. “Analysis of the marble buryingresponse: Marbles serve to measure digging rather than evoke burying”,Behavioural Pharmacology 6: 24-31, (1995)) and due to thepharmacological effects of clinical standards (c.f., Njung'E K. HandleySL. “Evaluation of marble-burying behavior as a model of anxiety”,Pharmacology, Biochemistry & Behavior. 38: 63-67, (1991)); Borsini F.,Podhorna J., and Marazziti, D. “Do animal models of anxiety predictanxiolytic effects of antidepressants?”, Psychopharmacology 163:121-141, (2002)). Thus, drugs used in the treatment of generalizedanxiety in humans (e.g. benzodiazepines) as well as compounds used totreat OCD (e.g. SSRIs like fluoxetine) decrease burying.

House experimentally-naïve male, NIH Swiss mice (Harlan Sprague-Dawley,Indianapolis, Ind.) weighing between 28-35 g in groups of 12 for atleast three days prior to testing in a vivarium with 12 h light and darkcycles. Conduct experiments during the light cycle in a dimly litexperimental testing room. Dose mice with vehicle or test compound and,after a specified pretreatment interval (generally 30 min.), place eachmouse individually on a rotorod (Ugo Basile 7650) operating at a speedof 6 revolutions/min. and observe for falling. After 2 min. on therotorod, place the mice individually in a 17×28×12 cm high plastic tubwith 5 mm sawdust shavings on the floor that are covered with 20 bluemarbles (1.5 cm diameter) placed in the center. After 30 min., count thenumber of marbles buried (2/3 covered with sawdust). Assess the testcompound's effect on marble burying with Dunnett's test and the effecton rotorod performance by Fisher's exact test.

Clinically effective standard compounds suppress marble burying at dosesthat are devoid of motor-impairing effects as measured on the rotorod.The in vivo efficacy of 5HT_(2C) compounds at the 5HT_(2C) receptor isconfirmed by the prevention of effects of the 5HT_(2C) agonists onmarble burying by co-administration of the 5HT_(2C) receptor antagonist,6-chloro-5-methyl-N-{2-[(2-methylpyridin-3-yl-oxy)pyridin-5-yl]aminocarbonyl}-2,3-dihydroindole.

Representative compounds of the present invention are assayed in themarble burying assay essentially as described and are surprisingly foundto reduce burying behavior in the test mice. The reduction of buryingbehavior is found to be blocked by co-administration of the 5-HT_(2C)antagonist. In contrast to the compounds of the present invention, theanxiolytic compound chlordiazepoxide and the antipsychotic compoundchlorpromazine decrease marble burying only at doses that also disruptrotorod performance.

Nestlet Shredding

Mice naturally will construct nests of material available in theirliving environment. Since this behavior is obsessive in nature, it hasbeen used to model OCD (Xia Li, Denise Morrow and Jeffrey M. Witkin,“Decreases in nestlet shredding of mice by serotonin uptake inhibitors:comparison with marble burying”, Psychopharmacology, submitted Jul. 14,2003). House experimentally-naïve male, NIH Swiss mice (HarlanSprague-Dawley, Indianapolis, Ind.) weighing between 28-35 g in groupsof 12 for at least three days prior to testing in a vivarium with a 12 hlight/dark cycle. Conduct experiments during the light cycle in anexperimental room with normal overhead fluorescent lighting. Dose micewith vehicle or test compound and after a specified pretreatmentinterval (generally 30 min.), place the mice individually in a 17×28×12cm high plastic tub with about 5 mm sawdust shavings on the floor alongwith a pre-weighed multi-ply gauze pad (51 mm square). After 30 min.,weigh the remainder of the gauze pad not removed by the mouse. Determinethe weight of the gauze used for nestlet construction by subtraction.Compare the results for test compound treated mice to the results forvehicle control treated mice with Dunnett's test.

Clinically effective OCD treatment standard compounds suppress nestletshredding at doses that are devoid of motor-impairing effects asmeasured by the rotorod test. The in vivo efficacy of 5HT_(2C) compoundsat the 5HT_(2C) receptor is confirmed bay the prevention of effects ofthe 5HT_(2C) agonists on nestlet shredding by co-administration of the5HT_(2C) receptor antagonist,6-chloro-5-methyl-N-{2-[(2-methylpyridin-3-yl-oxy)pyridin-5-yl]aminocarbonyl}-2,3-dihydroindole.

Representative compounds of the present invention are assayedessentially as described above and are surprisingly found to suppressnestlet shredding at doses that are devoid of motor-impairing effects asmeasured by the rotorod test.

In contrast to the compounds of the present invention, the anxiolyticchlordiazepoxide and the psychomotor stimulant d-amphetamine decreasesnestlet shredding only at doses that produce motoric side effects(depression or stimulation, respectively).

Schedule-Induced Polydipsia

Food-deprived rats exposed to intermittent presentations of food willdrink amounts of water that are far in excess of their normal dailyintake and in excess of their intake when given all of their food at onetime (Falk J L. “Production of polydipsia in normal rats by anintermittent food schedule”, Science 133: 195-196, (1961)). Thisexcessive behavior is persistent and has been used to model OCD.

Maintain Wistar rats on a food restricted diet (to maintain 85% freefeeding weight), but with free access to water. Train the rats in abehavioral testing chamber to press a lever to receive a food pelletunder a fixed interval schedule, such that the rats are rewarded with a45 mg food pellet the first time they press a lever after a 120 secondinterval has elapsed. The fixed interval is then reset to 120 secondsand the process repeated. Thus, during a 90 min. test session, the ratscan earn a maximum of 45 pellets. The behavioral chamber is alsoequipped with a water bottle that is weighed before and after thesession to determine the amount of water consumed.

Administer test compounds on Tuesdays and Fridays. Determine control dayperformances on Thursdays. Administer compounds either orally at 60 min.before the beginning of a test session, or subcutaneously at 20 min.before the beginning of a test session. Compare the rates of leverpressing and water consumption for each animal's performance duringsessions after test compound treatment with that animal's performanceduring control sessions, expressed as a percent of the control rate.Average the individual percent of control rates for each dose andcalculate the standard error of the mean.

Clinically effective OCD treatment standard compounds (e.g.chlomipramine, fluoxetine) suppress schedule-induced polydipsia withoutproducing notable changes in motor patterns, food intake, or behaviorthe following day. The in vivo efficacy of 5HT_(2C) compounds at the5HT_(2C) receptor is confirmed by the prevention of effects of the5HT_(2C) agonists on excessive drinking by co-administration of the5HT_(2C) receptor antagonist,6-chloro-5-methyl-N-{2-[(2-methylpyridin-3-yl-oxy)pyridin-5-yl]aminocarbonyl}-2,3-dihydroindole.

Representative compounds of the present invention are assayed in theschedule-induced polydipsia assay essentially as described above and aresurprisingly found to suppress schedule-induced polydipsia withoutproducing notable changes in motor patterns, food intake, or behaviorthe following day. The behavior suppression is blocked byco-administration of the 5-HT_(2C) antagonist.

In contrast to the compounds of the present invention, the psychomotorstimulant d-amphetamine decreases excessive drinking only atbehaviorally stimulating doses and these effects are not prevented bythe 5HT_(2C) receptor antagonist.

While it is possible to administer compounds employed in the methods ofthis invention directly without any formulation, the compounds areusually administered in the form of pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and at least onecompound of Formula I or a pharmaceutically acceptable salt thereof.These compositions can be administered by a variety of routes includingoral, rectal, transdermal, subcutaneous, intravenous, intramuscular, andintranasal. The compounds employed in the methods of this invention areeffective as both injectable and oral compositions. Such compositionsare prepared in a manner well known in the pharmaceutical art. See, e.g.REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).

In making the compositions employed in the present invention the activeingredient is usually mixed with at least one excipient, diluted by atleast one excipient, or enclosed within such a carrier which can be inthe form of a capsule, sachet, paper or other container. When theexcipient serves as a diluent, it can be a solid, semi-solid, or liquidmaterial, which acts as a vehicle, carrier or medium for the activeingredient. Thus, the compositions can be in the form of tablets, pills,powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions,solutions, syrups, aerosols (as a solid or in a liquid medium),ointments containing for example up to 10% by weight of the activecompound, soft and hard-gelatin capsules, suppositories, sterileinjectable solutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the compound toprovide the appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, itordinarily is milled to a particle size of less than 200 mesh. If theactive compound is substantially water soluble, the particle size isnormally adjusted by milling to provide a substantially uniformdistribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxybenzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 0.05 to about 100 mg, more usually about1.0 to about 30 mg, of the active ingredient. The term “unit dosageform” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The compounds are generally effective over a wide dosage range. Forexamples, dosages per day normally fall within the range of about 0.01to about 30 mg/kg. In the treatment of adult humans, the range of about0.1 to about 15 mg/kg/day, in single or divided dose, is especiallypreferred. However, it will be understood that the amount of thecompound actually administered will be determined by a physician, in thelight of the relevant circumstances, including the condition to betreated, the chosen route of administration, the actual compound orcompounds administered, the age, weight, and response of the individualpatient, and the severity of the patient's symptoms, and therefore theabove dosage ranges are not intended to limit the scope of the inventionin any way. In some instances dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed.

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Under some circumstances, it will be desirable or necessary to introducethe pharmaceutical composition to the brain, either directly orindirectly. Direct techniques usually involve placement of a drugdelivery catheter into the host's ventricular system to bypass theblood-brain barrier. One such implantable delivery system, used for thetransport of biological factors to specific anatomical regions of thebody, is described in U.S. Pat. No. 5,011,472, issued Apr. 30, 1991,which is herein incorporated by reference.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.Latentiation is generally achieved through blocking of the hydroxy,carbonyl, sulfate, and primary amine groups present on the drug torender the drug more lipid soluble and amenable to transportation acrossthe blood-brain barrier. Alternatively, the delivery of hydrophilicdrugs may be enhanced by intra-arterial infusion of hypertonic solutionswhich can transiently open the blood-brain barrier.

The type of formulation employed for the administration of the compoundsemployed in the methods of the present invention may be dictated by theparticular compound employed, the type of pharmacokinetic profiledesired from the route of administration, and the state of the patient.

1. A compound of Formula J:

where: R¹ is hydrogen, fluoro, or (C₁-C₃)alkyl; R², R³, and R⁴ are eachindependently hydrogen, methyl, or ethyl; R⁵ is hydrogen, fluoro,methyl, or ethyl; R⁶ is —C≡C—R¹⁰, —O—R¹², —S—R¹⁴, or —NR²⁴R²⁵; R⁷ ishydrogen, halo, cyano, (C₁-C₆)alkyl optionally substituted with 1 to 6fluoro substituents, (C₂-C₆)alkenyl optionally substituted with 1 to 6fluoro substituents, (C₃-C₇)cycloalkyl, (C₁-C₆)alkoxy optionallysubstituted with 1 to 6 fluoro substituents, (C₁-C₆)alkylthio optionallysubstituted with 1 to 6 fluoro substituents, Ph¹-(C₀-C₃)alkyl,Ph¹-(C₀-C₃)alkyl-O—, or Ph¹-(C₀-C₃)alkyl-S—; R⁸ is hydrogen, halo,cyano, or —SCF₃; R⁹ is hydrogen; R¹⁰ is —CF₃, ethyl substituted with 1to 5 fluoro substitutents, (C₃-C₆) alkyl optionally substituted with 1to 6 fluoro substituents, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl,Ar¹—(C₀-C₃)alkyl, Ph¹-(C₀-C₃)alkyl, or3-(C₁-C₄)alkyl-2-oxo-imidazolidin-1-yl-(C₁-C₃)alkyl; R¹² isPh²-(C₁-C₃)alkyl, Ar²—(C₁-C₃)alkyl, (C₁-C₆)alkyl-S—(C₂-C₆)alkyl,(C₃-C₇)cycloalkyl-S—(C₂-C₆)alkyl, phenyl-S—(C₂-C₆)alkyl,Ph²-S—(C₂-C₆)alkyl, phenylcarbonyl-(C₁-C₃)alkyl, Ph²-C(O)—(C₁-C₃)alkyl,(C₁-C₆)alkoxycarbonyl(C₃-C₆)alkyl, (C₃-C₇)cycloalkyl-OC(O)—(C₃-C₆)alkyl,phenyloxycarbonyl-(C₃-C₆)alkyl, Ph²-OC(O)—(C₃-C₆)alkyl,Ar²—OC(O)—(C₃-C₆)alkyl, (C₃-C₇)cycloalkyl-NH—C(O)—(C₂-C₄)alkyl-,Ph¹-NH—C(O)—(C₂-C₄)alkyl-, Ar²—NH—C(O)—(C₂-C₄)alkyl-, orR¹³—C(O)NH—(C₂-C₄)alkyl; R¹³ is (C₃-C₇)cycloalkyl(C₀-C₃)alkyl, Ph¹, Ar²,or (C₁-C₃)alkoxy optionally substituted with 1 to 6 fluoro substituents,Ph¹-NH— or N-linked Het¹; R¹⁴ is Ar² which is not N-linked to the sulfuratom, Ph², R¹⁵-L-, tetrahydrofuranyl, tetrahydropyranyl, orphenyl-methyl substituted on the methyl moiety with a substituentselected from the group consisting of (C₁-C₃)-n-alkyl substituted withhydroxy, (C₁-C₃)alkyl-O—(C₁-C₂)-n-alkyl,(C₁-C₃)alkyl-C(O)—(C₀-C₂)-n-alkyl, and(C₁-C₃)alkyl-O—C(O)—(C₀-C₂)-n-alkyl, wherein when R¹⁴ is Ph² or Ar²,wherein Ar² is pyridyl, then R¹⁴ may also, optionally be substitutedwith phenyl-CH═CH— or phenyl-C≡C—, said phenyl-CH═CH— or phenyl-C≡C—being optionally further substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, cyano, —SCF₃,(C₁-C₆)alkyl optionally further substituted with 1 to 6 fluorosubstituents, and (C₁-C₆)alkoxy optionally further substituted with 1 to6 fluoro substituents, and wherein when Ar² is pyridyl, the pyridyl mayalternatively, optionally be substituted with R²⁸R²⁹N—C(O)—, andoptionally further substituted with one methyl, —CF₃, cyano, or —SCF₃substituent, or with 1 to 2 halo substituents, and wherein thetetrahydrofuranyl and tetrahydropyranyl may optionally be substitutedwith an oxo substituent, or with one or two groups independentlyselected from methyl and —CF₃; R¹⁵ is —OR⁶, cyano, —SCF₃, Ph², Ar²,quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, phthalimido,benzothiophenyl optionally substituted at the 2-position with phenyl orbenzyl, benzothiazolyl optionally substituted at the 2-position withphenyl or benzyl, benzothiadiazolyl optionally substituted with phenylor benzyl, 2-oxo-dihydroindol-1-yl optionally substituted at the 3position with gem dimethyl or (C₁-C₆)alkyl optionally furthersubstituted with 1 to 6 fluoro substituents, 2-oxo-dihydroindol-5-yloptionally substituted at the 3 position with gem dimethyl or(C₁-C₆)alkyl optionally further substituted with 1 to 6 fluorosubstituents, 2-oxo-imidazolidin-1-yl optionally substituted at the 3position with gem dimethyl or (C₁-C₆)alkyl optionally furthersubstituted with 1 to 6 fluoro substituents, 2-oxo-tetrahydropyrimidinyloptionally substituted at the 3 or 4 position with gem dimethyl or(C₁-C₆)alkyl optionally further substituted with 1 to 6 fluorosubstituents, 2-oxo-tetrahydroquinolin-1-yl optionally substituted atthe 3 position with gem dimethyl or (C₁-C₆)alkyl optionally furthersubstituted with 1 to 6 fluoro substituents,2-oxo-dihydrobenzimidazol-1-yl optionally substituted at the 3 positionwith gem dimethyl or (C₁-C₆)alkyl optionally further substituted with 1to 6 fluoro substituents, —NR¹⁷R¹⁸, —C(O)R²², or a saturated heterocyleselected from the group consisting of pyrrolidinyl, piperidinyl,morpholinyl, and thiomorpholinyl, tetrahydrofuranyl, andtetrahydropyranyl, wherein Ph² and Ar² when Ar² is pyridyl, may alsooptionally be substituted with phenyl-CH═CH— or phenyl-C≡C—, saidphenyl-CH═CH— and phenyl-C≡C— being optionally further substituted onthe phenyl moiety with 1 to 3 substituents independently selected fromthe group consisting of halo, cyano, —SCF₃, (C₁-C₆)alkyl optionallyfurther substituted with 1 to 6 fluoro substituents, and (C₁-C₆)alkoxyoptionally further substituted with 1 to 6 fluoro substituents, andwherein Ar² may alternatively, optionally be substituted with asubstituent selected from the group consisting of(C₃-C₇)cycloalkyl-(C₀-C₃)alkyl, Het¹-(C₀-C₃)alkyl, pyridyl-(C₀-C₃)alkyl,and phenyl-(C₀-C₃)alkyl, and optionally further substituted with onemethyl, —CF₃, cyano, or —SCF₃ substituent, or with 1 to 2 halosubstituents, said pyridyl-(C₀-C₃)alkyl and phenyl-(C₀-C₃)alkyloptionally being further substituted with 1-3 substituents independentlyselected from halo, —CH₃, —OCH₃, —CF₃, —OCF₃, —CN, and —SCF₃, andwherein when Ar² is pyridyl, the pyridyl may alternatively, optionallybe substituted with R²⁸R²⁹N—C(O)—, or (C₁-C₆)alkyl-C(O)— optionallysubstituted with 1 to 6 fluoro substituents, and may be optionallyfurther substituted with one methyl, —CF₃, cyano, or —SCF₃ substituent,or with 1 to 2 halo substituents, and wherein when Ar² is thiazolyl, thethiazolyl may alternatively, optionally be substituted with(C₃-C₇)cycloalkyl-(C₀-C₃)alkyl-NH—, and wherein the pyrrolidinyl,piperidinyl, morpholinyl, and thiomorpholinyl is substituted with oxo-on a carbon atom adjacent to the ring nitrogen atom, or is N-substitutedwith a substituent selected from the group consisting of(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl,(C₃-C₇)cycloalkyl(C₀-C₃)alkyl-C(O)—,(C₃-C₇)cycloalkyl(C₀-C₃)alkyl-S(O)₂—, Ph¹-(C₀-C₃)alkyl-C(O)—, andPh¹-(C₀-C₃)alkyl-S(O)₂—, and may optionally be further substituted with1 or 2 methyl or —CF₃ substituents, and when oxo-substituted, mayoptionally be further N-substituted with a substituent selected from thegroup consisting of (C₁-C₆)alkyl optionally further substituted with 1to 6 fluoro substituents, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl, andPh¹-(C₀-C₃)alkyl, and wherein tetrahydrofuranyl and tetrahydropyranylmay optionally be substituted with an oxo substituent, and/or with oneor two groups independently selected from methyl and —CF₃; L is branchedor unbranched (C₁-C₆)alkylene, except when R¹⁵ is —NR¹⁷R¹⁸ orAr²-N-linked to L, in which case L is branched or unbranched(C₂-C₆)alkylene, and when L is methylene or ethylene, L may optionallybe substituted with gem-ethano or with 1 to 2 fluoro substituents, andwhen R¹⁵ is Ph², Ar², or a saturated heterocycle, L may alternatively,optionally be substituted with a substituent selected from the groupconsisting of hydroxy, cyano, —SCF₃, (C₁-C₆)alkoxy optionally furthersubstituted with 1 to 6 fluoro substituents, (C₁-C₆)alkoxycarbonyloptionally further substituted with 1 to 6 fluoro substituents,(C₁-C₆)alkylcarbonyloxy optionally further substituted with 1 to 6fluoro substituents, (C₃-C₇)cycloalkyl-(C₀-C₃)alkyl-O—,(C₃-C₇)cycloalkyl-(C₀-C₃)alkyl-O—C(O)—, and(C₃-C₇)cycloalkyl-(C₀-C₃)alkyl-C(O)—O—; R¹⁶ is hydrogen, (C₁-C₆)alkyloptionally substituted with 1 to 6 fluoro substituents,(C₁-C₆)alkylcarbonyl, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl,(C₃-C₇)cycloalkyl(C₀-C₃)alkyl-C(O)—, Ph¹-(C₀-C₃)alkyl,Ph¹-(C₀-C₃)alkyl-C(O)—, Ar²—(C₀-C₃)alkyl, or Ar²—(C₀-C₃)alkyl-C(O)—, R¹⁷is (C₁-C₄)alkyl optionally substituted with 1 to 6 fluoro substituents,t-butylsulfonyl, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-C(O)—,(C₃-C₇)cycloalkyl(C₀-C₃)alkyl-sulfonyl, Ph¹-(C₀-C₃)alkyl,Ph¹-(C₀-C₃)alkyl-C(O)—, Ph¹-(C₀-C₃)alkylsulfonyl, Ar²—(C₀-C₃)alkyl,Ar²—(C₀-C₃)alkyl-C(O)—, Ar²—(C₀-C₃)alkylsulfonyl, R¹⁹OC(O)—, orR²⁰R²¹NC(O)—; R₁₈ is hydrogen or (C₁-C₄)alkyl optionally substitutedwith 1 to 6 fluoro substituents, or R¹⁷ and R¹⁸, taken together with thenitrogen atom to which they are attached form Het¹ where Het¹ issubstituted with oxo- on a carbon atom adjacent to the ring nitrogenatom, or R¹⁷ and R¹⁸, taken together with the nitrogen atom to whichthey are attached, form an aromatic heterocycle selected from the groupconsisting of pyrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, and1,2,4-triazolyl, said aromatic heterocycle optionally being substitutedwith 1 to 2 halo substituents, or substituted with 1 to 2 (C₁-C₄)alkylsubstituents optionally further substituted with 1 to 3 fluorosubstituents, or mono-substituted with fluoro, nitro, cyano, —SCF₃, or(C₁-C₄)alkoxy optionally further substituted with 1 to 3 fluorosubstituents, and optionally further substituted with a (C₁-C₄)alkylsubstituent optionally further substituted with 1 to 3 fluorosubstituents; R¹⁹ is (C₁-C₆)alkyl optionally substituted with 1 to 6fluoro substituents, (C₃-C₇)cycloalkyl-(C₀-C₃)alkyl, Ar²—(C₀-C₃)alkyl,or Ph¹-(C₀-C₃)alkyl, R²⁰ is (C₁-C₆)alkyl optionally substituted with 1to 6 fluoro substituents, (C₃-C₇)cycloalkyl-(C₀-C₃)alkyl,Ar²—(C₀-C₃)alkyl, or Ph¹-(C₀-C₃)alkyl, R²¹ is hydrogen or (C₁-C₄)alkyloptionally substituted with 1 to 6 fluoro substituents, or R²⁰ and R²¹,taken together with the nitrogen atom to which they are attached, formHet¹; R²² is (C₁-C₆)alkyl optionally substituted with 1 to 6 fluorosubstituents, (C₃-C₇)cycloalkyl-(C₀-C₃)alkyl, R²³—O—, Ph¹-(C₀-C₃)alkyl,Ar²—(C₀-C₃)alkyl, or R³²R³³N—; R²³ is (C₁-C₆)alkyl optionallysubstituted with 1 to 6 fluoro substituents,(C₃-C₇)cycloalkyl-(C₀-C₃)alkyl, Ph¹-(C₀-C₃)alkyl, or Ar²—(C₀-C₃)alkyl;R²⁴ is (C₁-C₆)alkoxy(C₂-C₅)alkyl optionally substituted with 1 to 6fluoro substituents, (C₁-C₆)alkylthio(C₂-C₅)alkyl optionally substitutedwith 1 to 6 fluoro substituents,(C₃-C₇)cycloalkyl(C₀-C₁)alkyl-O—(C₁-C₅)alkyl,(C₃-C₇)cycloalkyl(C₀-C₁)alkyl-S—(C₁-C₅)alkyl, phenyl(C₁-C₃) n-alkyl,Ph²-(C₁-C₃)-n-alkyl, Ar²(C₀-C₃) n-alkyl,phenyl(C₀-C₁)alkyl-O—(C₁-C₅)alkyl, phenyl(C₀-C₁)alkyl-S—(C₁-C₅)alkyl,Ph¹-(C₀-C₁)alkyl-C(O)NH—(C₂-C₄)alkyl,Ph¹-(C₀-C₁)alkyl-NH—C(O)NH—(C₂-C₄)alkyl,pyridyl-(C₀-C₁)alkyl-C(O)NH—(C₂-C₄)alkyl,pyridyl-(C₀-C₁)alkyl-NH—C(O)NH—(C₂-C₄)alkyl, or Ar³(C₁-C₂)alkyl, whereAr³ is a bi-cyclic moiety selected from a group consisting of indanyl,indolyl, dihydrobenzofuranyl, benzofuranyl, benzothiophenyl,benzoxazolyl, benzothiazolyl, benzo[1,3]dioxolyl, naphthyl,dihydrobenzopyranyl, quinolinyl, isoquinolinyl, andbenzo[1,2,3]thiadiazolyl, said Ar³ optionally being substituted with(C₁-C₆)alkyl optionally further substituted with 1 to 6 fluorosubstituents, phenyl(C₀-C₁)alkyl optionally further substituted with 1to 6 fluoro substituents, or substituted with(C₃-C₇)cycloalkyl(C₀-C₃)alkyl, or substituted with 1-3 substituentsindependently selected from the group consisting of halo, oxo, methyl,and —CF₃, said phenyl(C₁-C₃) n-alkyl, Ph²-(C₁-C₃) n-alkyl, or Ar²(C₀-C₃)n-alkyl optionally being substituted on the n-alkyl moiety when presentwith (C₁-C₃)alkyl, dimethyl, gem-ethano, 1 to 2 fluoro substituents, or(C₁-C₆)alkyl-C(O)—, said Ar²(C₀-C₃) n-alkyl being alternativelyoptionally substituted with a substituent selected from the groupconsisting of (C₃-C₇)cycloalkyl-(C₀-C₃)alkyl, Het¹-(C₀-C₃)alkyl,pyridyl-(C₀-C₃)alkyl, phenyl-(C₀-C₃)alkyl, pyridyl-(C₀-C₃)alkyl-NH—,phenyl-(C₀-C₃)alkyl-NH—, (C₁-C₆)alkyl-S—, and(C₃-C₇)cycloalkyl-(C₀-C₃)alkyl-S—, and optionally further substitutedwith one methyl, —CF₃, cyano, or —SCF₃ substituent, or with 1 to 2 halosubstituents, said pyridyl-(C₀-C₃)alkyl and phenyl-(C₀-C₃)alkyloptionally being further substituted with 1-3 substituents independentlyselected from halo, —CH₃, —OCH₃, —CF₃, —OCF₃, —CN, and —SCF₃, and saidPh²-(C₁-C₃) n-alkyl and Ar²(C₀-C₃) n-alkyl where Ar² is pyridyl, alsooptionally being substituted on the phenyl or Ar² moiety, respectively,with phenyl-CH═CH— or phenyl-C≡C—, said phenyl-CH═CH— or phenyl-C≡C—being optionally further substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, cyano, —SCF₃,(C₁-C₆)alkyl optionally further substituted with 1 to 6 fluorosubstituents, and (C₁-C₆)alkoxy optionally further substituted with 1 to6 fluoro substituents, and said Ar²(C₀-C₃) n-alkyl where Ar² is pyridyl,alternatively, optionally being substituted with (C₁-C₆)alkyl-C(O)— orR²⁸R²⁹N—C(O)—, and optionally further substituted with one methyl, —CF₃,cyano, or —SCF₃ substituent, or with 1 to 2 halo substituents, saidphenyl(C₀-C₁)alkyl-O—(C₁-C₅)alkyl, or phenyl(C₀-C₁)alkyl-S—(C₁-C₅)alkyloptionally being substituted on the phenyl moiety with (C₁-C₂)—S(O)₂—,or with 1 to 5 independently selected halo substituents, or with 1 to 3substituents independently selected from the group consisting of halo,cyano, —SCF₃, (C₁-C₆)alkyl optionally further substituted with 1 to 6fluoro substituents, and (C₁-C₆)alkoxy optionally further substitutedwith 1 to 6 fluoro substituents, and saidpyridyl-(C₀-C₁)alkyl-C(O)NH—(C₂-C₄)alkyl andpyridyl-(C₀-C₁)alkyl-NH—C(O)NH—(C₂-C₄)alkyl optionally being substitutedon the pyridyl moiety with methyl, —CF₃, or 1 to 3 halo substituents;R²⁵ is hydrogen, (C₁-C₃)alkyl optionally substituted with 1 to 6 fluorosubstituents, or alkyl; R²⁶ is hydrogen, (C₁-C₄)alkyl optionallysubstituted with 1 to 6 fluoro substituents,(C₃-C₇)cycloalkyl(C₀-C₃)alkyl, Ph¹-(C₀-C₃)alkyl, or Het²-(C₀-C₃)alkyl;R²⁷ is hydrogen or (C₁-C₄)alkyl optionally substituted with 1 to 6fluoro substituents, or R²⁶ and R²⁷, taken together with the nitrogenatom to which they are attached, form Het¹; R²⁸ is (C₁-C₆)alkyloptionally substituted with 1 to 6 fluoro substituents,(C₃-C₇)cycloalkyl-(C₀-C₃)alkyl, tetrahydropyran-3-yl(C₀-C₃)alkyl,tetrahydropyran-4-yl(C₀-C₃)alkyl, tetrahydrofuranyl(C₀-C₃)alkyl,Ph¹-(C₀-C₂) n-alkyl, or Ar²—(C₀-C₂) n-alkyl, said Ph¹-(C₀-C₂) n-alkyland Ar²—(C₀-C₂) n-alkyl optionally being substituted on the alkyl moietywhen present with (C₁-C₃)alkyl, dimethyl, or gem-ethano; R²⁹ is hydrogenor (C₁-C₃)alkyl; R³⁰ is hydrogen, (C₁-C₆)alkyl optionally substitutedwith 1 to 6 fluoro substituents, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl,Ph¹-(C₀-C₃)alkyl, or Ar²(C₀-C₃)alkyl, R³¹ is hydrogen or (C₁-C₆)alkyloptionally substituted with 1 to 6 fluoro substituents, or R³⁰ and R³¹,taken together with the nitrogen atom to which they are attached, formHet¹, said Het¹ also optionally being substituted with phenyl optionallyfurther substituted with 1 to 3 halo substituents; R³² and R³³ are eachindependently hydrogen or (C₁-C₆)alkyl optionally substituted with 1 to6 fluoro substituents, or R³² and R³³, taken together with the nitrogenatom to which they are attached, form Het¹, or R³² is Ph¹(C₀-C₁)alkylprovided that R³³ is hydrogen; Ar¹ is an aromatic heterocyclesubstituent selected from the group consisting of furanyl, thiophenyl,thiazolyl, oxazolyl, isoxazolyl, pyridyl, and pyridazinyl, any of whichmay optionally be substituted with 1 to 3 substituents independentlyselected from the group consisting of halo, (C₁-C₃)alkyl, (C₁-C₃)alkoxy,—CF₃, —O—CF₃, nitro, cyano, and trifluoromethylthio; Ar² is an aromaticheterocycle substituent selected from the group consisting of pyrrolyl,pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl,oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyridazinyl, andbenzimidazolyl, any of which may optionally be substituted with 1 to 3substituents independently selected from the group consisting of halo,cyano, —SCF₃, (C₁-C₆)alkyl optionally further substituted with 1 to 6fluoro substituents, and (C₁-C₆)alkoxy optionally further substitutedwith 1 to 6 fluoro substituents, and wherein pyridyl and pyridazinyl mayalso optionally be substituted with (C₁-C₆)alkylamino optionally furthersubstituted with 1 to 6 fluoro substituents,(C₃-C₇)cycloalkyl(C₀-C₃)alkyl, or (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-amino;Het¹ is a saturated, nitrogen-containing heterocycle substituentselected from the group consisting of azetidinyl, pyrrolidinyl,piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl,homomorpholinyl, and homothiomorpholinyl, any of which may optionally besubstituted with (C₁-C₆)alkyl or with 2 methyl substituents; Het² is asaturated, oxygen-containing heterocycle substituent selected from thegroup consisting of tetrahydrofuranyl, tetrahydropyranyl, and oxepinyl,any of which may optionally be substituted with (C₁-C₆)alkyl or with 2methyl substituents; Ph¹ is phenyl optionally substituted with 1 to 5independently selected halo substituents, or with 1 to 3 substituentsindependently selected from the group consisting of halo, cyano, —SCF₃,(C₁-C₆)alkyl optionally further substituted with 1 to 6 fluorosubstituents, and (C₁-C₆)alkoxy optionally further substituted with 1 to6 fluoro substituents; Ph² is phenyl substituted with: a) 1 to 5independently selected halo substituents; or b) 1 to 3 substituentsindependently selected from the group consisting of halo, cyano, —SCF₃,nitro, hydroxy, (C₁-C₆)alkyl optionally further substituted with 1 to 6fluoro substituents, and (C₁-C₆)alkoxy optionally further substitutedwith 1 to 6 fluoro substituents; or c) 0, 1, or 2 substituentsindependently selected from the group consisting of halo, cyano, —SCF₃,methyl, —CF₃, methoxy, —OCF₃, nitro, and hydroxy, together with onesubstituent selected from the group consisting of i) (C₁-C₁₀)alkyloptionally further substituted with 1 to 6 fluoro substituents ormono-substituted with hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl-C(O)—,(C₁-C₆)alkyl-S(O)—, (C₁-C₆)alkyl-S(O)₂—,(C₃-C₇)cycloalkyl(C₀-C₃)alkyloxy, (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-S(O)—,(C₃-C₇)cycloalkyl(C₀-C₃)alkyl-S(O)₂—, Het²-(C₀-C₃)alkyloxy,Het²-(C₀-C₃)alkyl-S(O), Het²-(C₀-C₃)alkyl-S(O)₂, Ph¹-(C₀-C₃)alkyloxy,Ph¹-(C₀-C₃)alkyl-S(O)—, Ph¹-(C₀-C₃)alkyl-S(O)₂—, ii)C₁-C₁₀)alkoxy-(C₀-C₃)alkyl optionally further substituted with 1 to 6fluoro substituents, and optionally further substituted with hydroxy,iii) (C₁-C₆)alkyl-C(O)—(C₀-C₃)alkyl optionally further substituted with1 to 6 fluoro substituents, iv) carboxy, v) (C₁-C₆)alkoxycarbonyloptionally further substituted with 1 to 6 fluoro substituents, vi)(C₁-C₆)alkyl-C(O)—(C₀-C₃)—O— optionally further substituted with 1 to 6fluoro substituents, vii) (C₁-C₆)alkylthio-(C₀-C₃)alkyl optionallyfurther substituted with 1 to 6 fluoro substituents, viii)(C₁-C₆)alkylsulfinyl-(C₀-C₃)alkyl optionally further substituted with 1to 6 fluoro substituents, ix) (C₁-C₆)alkylsulfonyl-(C₀-C₃)alkyloptionally further substituted with 1 to 6 fluoro substituents, x)(C₁-C₆)alkylsulfonyl-(C₀-C₁)alkyl-O— optionally further substituted with1 to 6 fluoro substituents, xi) (C₃-C₇)cycloalkyl(C₀-C₃)alkyl,optionally further substituted on the cycloalkyl with 1 to 4substituents selected from methyl and fluoro, xii)(C₃-C₇)cycloalkyl(C₀-C₃)alkyl-O—, optionally further substituted on thecycloalkyl with 1 to 4 substituents selected from methyl and fluoro,xiii) (C₃-C₇)cycloalkyl(C₀-C₃)alkyl-C(O)—, xiv)(C₃-C₇)cycloalkyl(C₀-C₃)alkyl-O—C(O)—, xv)(C₃-C₇)cycloalkyl(C₀-C₃)alkyl-S—(C₀-C₃)alkyl, xvi)(C₃-C₇)cycloalkyl(C₀-C₃)alkyl-S(O)—(C₀-C₃)alkyl, xvii)(C₃-C₇)cycloalkyl(C₀-C₃)alkyl-S(O)₂—(C₀-C₃)alkyl, xviii)Ph¹-(C₀-C₃)alkyl, optionally substituted on the alkyl moiety with 1 to 2fluoro substituents, xix) Ph¹-(C₀-C₃)alkyl-O—, optionally substituted onthe alkyl moiety with 1 to 2 fluoro substituents xx)Ph¹-(C₀-C₃)alkyl-C(O)—, xxi) Ph¹-(C₀-C₃)alkyl-O—C(O)—, xxii)Ph¹-(C₀-C₃)alkyl-C(O)—(C₀-C₃)alkyl-O—, xxiii) Ph¹-(C₀-C₃)alkylthio,xxiv) Ph¹-(C₀-C₃)alkylsulfinyl, xxv) Ph¹-(C₀-C₃)alkylsulfonyl, xxvi)Ar²(C₀-C₃)alkyl, xxvii) Ar²(C₀-C₃)alkyl-O— xviii) Ar²(C₀-C₃)alkyl-S—,xxix) Ar²(C₀-C₃)alkyl-C(O)—, xxx) Ar²(C₀-C₃)alkyl-C(S)—, xxxi)Ar²—(C₀-C₃)alkylsulfinyl, xxxii) Ar²—(C₀-C₃)alkylsulfonyl, xxxiii)Het¹(C₀-C₃)alkyl-C(O)— optionally substituted on the Het¹ moiety withPh¹, xxxiv) Het¹(C₀-C₃)alkyl-C(S)— optionally substituted on the Het¹moiety with Ph¹, xxxv) N-linked Het¹-C(O)—(C₀-C₃)alkyl-O—, xxxvi)Het²-(C₀-C₃)alkyl, xxxvii) Het²-(C₀-C₃)alkyloxy, xxxviii)Het²-(C₀-C₃)alkyl-S—, xxxix) Het²-(C₀-C₃)alkyl-NH—, xl) R²⁶R²⁷N—, xli)R²⁸R²⁹N—(C₁-C₃)alkoxy, xlii) R²⁸R²⁹N—C(O)—, xliii)R²⁸R²⁹N—C(O)—(C₁-C₃)alkyl-O—, xliv) R²⁸R²⁹N—C(S)—, xlv) R³⁰R³¹N—S(O)₂—,xlvi) HON═C(CH₃)—, and xlvii) HON═C(Ph¹)-, or a pharmaceuticallyacceptable salt thereof, subject to the following provisos: a) no morethan two of R¹, R², R³, R⁴, and R⁵ may be other than hydrogen; b) whenR² is methyl, then R¹, R³, R⁴, and R⁵ are each hydrogen; c) when R³ ismethyl, then R² and R⁴ are each hydrogen.
 2. A compound according toclaim 1 wherein R⁷ is selected from halo, —CN, and CF₃.
 3. A compoundaccording to claim 1 wherein R⁷ is chloro.
 4. A compound according toclaim 1 wherein R⁶ is —C≡C—R¹⁰.
 5. A compound according to claim 1wherein R⁶ is —O—R¹².
 6. A compound according to claim 1 wherein R⁶ is—S—R¹⁴.
 7. A compound according to claim 6 wherein R⁶ is —S-L-R¹⁵.
 8. Acompound according to claim 7 wherein R¹⁵ is Ph² or Ar².
 9. A compoundaccording to claim 1 wherein R⁶ is —NR²⁴R²⁵.
 10. A compound according toclaim 9 wherein R²⁴ is Ph²-(C₁-C₃) n-alkyl-.
 11. A compound according toclaim 9 wherein R²⁴ is Ar²—(C₁-C₃) n-alkyl-.
 12. A compound according toclaim 9 wherein R²⁴ is Ph²-(C₁-C₃) n-alkyl- or Ar²—(C₁-C₃) n-alkyl-, andR²⁵ is hydrogen.
 13. (canceled)
 14. (canceled)
 15. A compound accordingto claim 1 wherein R¹, R², R³, R⁴, R⁵, and R⁸, are each hydrogen.
 16. Apharmaceutical composition comprising a compound according to claim 1 asan active ingredient in association with a pharmaceutically acceptablecarrier, diluent or excipient.
 17. (canceled)
 18. A method for thetreatment of obesity in mammals, comprising administering to a mammal inneed of such treatment an effective amount of a compound according toclaim
 1. 19. The method of claim 18, where the mammal is human.
 20. Amethod for the treatment of obsessive compulsive disorder in mammals,comprising administering to a mammal in need of such treatment aneffective amount of a compound according to claim
 1. 21. The method ofclaim 20, where the mammal is human.
 22. (canceled)
 23. (canceled)
 24. Amethod for the treatment of anxiety in mammals, comprising administeringto a mammal in need of such treatment an effective amount of a compoundaccording to claim
 1. 25. The method of claim 24, where the mammal ishuman. 26.-37. (canceled)